Pcmodel V 9.0

Transcript

PCMODEL V 9.0 Molecular Modeling Software for Windows Operating System Apple Macintosh OS Linux and Unix Serena Software Box 3076 Bloomington, IN 47402-3076 (812)-333-0823 © 1993-2004 Serena Software. All rights reserved. First Edition June 1998 Second Edition June 1999 Third Edition January 2001 Fourth Edition April 2002 Fifth Edition August 2003 Sixth Edition August 2004 Trademarks IBM and IBM PC are registered trademarks of International Business Machines Inc. Windows is a registered trademark of the Microsoft Corporation. Alchemy and Sybyl are registered trademarks of Tripos Associates, Inc. Chem-3D is a registered trademark of Cambridge Scientific Computing, Inc. ISIS is a trademark of MDL Information Systems, Inc. 2 License Agreement Serena Software provides these programs and licenses their use in your teaching and research. You assume responsibility for the use of the program to achieve your intended results. You may: 1. Use the programs on any machine or machines in your possession. 2. Copy the programs and source code into any machine readable form for backup or modification purposes in support of your use of the programs. 3. Modify the programs and source code or merge them into another program for your use. (Any portion of these programs or source code or merged programs resulting will continue to be subject to the terms and conditions of this agreement.) You may not: 1. Give copies of these programs to anyone else, unless you destroy all copies you have in any form. 2. Sell copies of these programs. 3. Use the programs on a network, unless others are prevented from accessing the programs. This license is effective until terminated. You may terminate it at any time by destroying the programs and source code together with all copies, modifications and merged portions in any form. These programs are provided "AS IS" and without warranty of any kind, either expressed or implied. The entire risk as to the quality and performance of the programs is with the user. Serena Software does not warrant the operation of the programs will be uninterrupted or error free. If Serena Software is unable to deliver a copy of the programs that is satisfactory, you may obtain a full refund by returning all the program materials and documentation within 30 days of date of delivery. These programs are intended for use in chemical research and teaching. Serena Software will not be liable in any event to you for any damages, including any lost profits, lost savings or other incidental or consequential damages arising out of the use or inability to use these programs even if Serena Software has been advised of the possibility of such damages, or for claim by any other party. 3 Table of Contents Table of Contents ....................................................................................................................................... 4 Chapter 1. Overview.................................................................................................................................. 9 1.1 Introduction ..................................................................................................................................... 9 1.2 Changes in Version 7 ........................................................................................................................ 9 1.3 Changes in Version 7.5 ..................................................................................................................... 9 1.40 Changes in Version 8.0 ................................................................................................................. 10 1.41 Changes in Version 8.5 ................................................................................................................. 10 1.42 Changes in Version 9.0 ................................................................................................................. 10 1.5 History............................................................................................................................................ 10 1.6 The PCMODEL Window............................................................................................................... 12 1.7 Definitions ..................................................................................................................................... 13 1.8 Closing Notes ................................................................................................................................. 13 Chapter 2. Installation.............................................................................................................................. 15 2.1 Windows Installation ...................................................................................................................... 15 2.2 Macintosh Installation..................................................................................................................... 15 2.3 Linux Installation............................................................................................................................ 16 2.4 General Comments ......................................................................................................................... 17 Chapter 3. Quick Summary of PCMODEL Menu Bar Functions .............................................................. 19 Chapter 4. Tutorials ................................................................................................................................. 25 4.1 Methylcyclohexane......................................................................................................................... 25 4.1.1 Drawing the Structure .............................................................................................................. 25 4.1.2 Building the Structure .............................................................................................................. 28 4.1.3 Minimizing and Adjusting the Structure ................................................................................... 29 4.2 Trans-Decalin ................................................................................................................................ 30 4.3 Special Options............................................................................................................................... 31 4.3.1 Compare .................................................................................................................................. 31 4.3.2 Rotational Energy Barriers ....................................................................................................... 32 4.4 Benzene and a Pi Calculation .......................................................................................................... 32 4.5 Biphenyl and a Pi Calculation ......................................................................................................... 32 4.6 Ferrocene - Using Metals and Coordination .................................................................................... 33 4.7 The Methanol dimer - Hydrogen Bonding and Docking .................................................................. 33 4.8 Substructures - Creation and Manipulation...................................................................................... 34 4.8.1 Building Polystryene using Dummy Atoms.............................................................................. 35 4.9 Diels-Alder Transition State............................................................................................................ 35 Chapter 5. Drawing Tools........................................................................................................................ 38 5.1.1 Select Atom ................................................................................................................................. 38 5.1.2 Select Bond.................................................................................................................................. 38 5.2 Draw............................................................................................................................................... 38 5.3 Build............................................................................................................................................... 39 5.4 Update ............................................................................................................................................ 39 5.5 H/AD.............................................................................................................................................. 39 5.6 Add_B ............................................................................................................................................ 39 5.7 In .................................................................................................................................................... 39 5.8 Out ................................................................................................................................................. 39 5.9 Del.................................................................................................................................................. 40 5.10 Move ............................................................................................................................................ 40 5.11 Rotate Bond .................................................................................................................................. 40 5.12 Query............................................................................................................................................ 40 5.13 PT................................................................................................................................................. 41 5.14 Metals........................................................................................................................................... 41 5.15 Rings ............................................................................................................................................ 42 5.16 AA................................................................................................................................................ 42 5.17 Su ................................................................................................................................................. 42 4 5.18 Nu................................................................................................................................................. 43 5.18 Organo Metallics Templates.......................................................................................................... 43 5.20 Transition State Templates............................................................................................................ 44 Chapter 6. Conformational Searching ....................................................................................................... 46 6.1 Setup Rings..................................................................................................................................... 47 6.2 Setup Bonds.................................................................................................................................... 48 6.3 Setup Query.................................................................................................................................... 48 6.4 Comparison Method........................................................................................................................ 49 6.5 Options ........................................................................................................................................... 50 6.6 Run GMMX ................................................................................................................................... 50 6.7 Run 2nd Cycle.................................................................................................................................. 51 6.8 Save Job ......................................................................................................................................... 51 6.9 Read Job ......................................................................................................................................... 51 Chapter 7. File Menu ................................................................................................................................ 53 7.1 Open............................................................................................................................................... 53 7.2 Save................................................................................................................................................ 56 7.3 Save Graphic .................................................................................................................................. 60 7.4 Save Movie..................................................................................................................................... 60 7.5 Print................................................................................................................................................ 60 7.6 Read pcmod.bak ............................................................................................................................. 61 7.7 Exit................................................................................................................................................. 61 Chapter 8 Edit Menu ................................................................................................................................ 63 8.1 Draw............................................................................................................................................... 63 8.2 Erase............................................................................................................................................... 64 8.3 Structure name................................................................................................................................ 64 8.4 Hide Hydrogens .............................................................................................................................. 64 8.5 Epimer ............................................................................................................................................ 64 8.6 Enatiomer ....................................................................................................................................... 64 8.7 Remove LP ..................................................................................................................................... 64 8.8 Retype ............................................................................................................................................ 64 8.9 Set Atom Type................................................................................................................................ 65 8.10 List Atom Types ........................................................................................................................... 65 8.11 Read Pcmod.out............................................................................................................................ 65 8.12 Read Pcmod.err............................................................................................................................. 65 8.13 Copy_To_Clipboard ..................................................................................................................... 65 8.14 Orient_XY Plane .......................................................................................................................... 65 8.15 Build Solvent Box/Solvate ............................................................................................................ 65 8.16 Build Periodic Box........................................................................................................................ 66 Chapter 9 View Menu............................................................................................................................... 69 9.1 Control Panel .................................................................................................................................. 69 9.2 Labels ............................................................................................................................................. 70 9.3 Mono/Stereo ................................................................................................................................... 71 9.4 Stick Figure .................................................................................................................................... 71 9.5 Ball and Stick ................................................................................................................................. 71 9.6 Pluto ............................................................................................................................................... 71 9.7 Tubes.............................................................................................................................................. 71 9.8 CPK_Surface .................................................................................................................................. 71 9.9 Dot_Surface.................................................................................................................................... 72 9.10 Ribbon .......................................................................................................................................... 72 9.11 Red/Green Stereo.......................................................................................................................... 72 9.12 Top View...................................................................................................................................... 72 9.13 Dipole Vector ............................................................................................................................... 72 Chapter 10 Compute and Force Field Menus ........................................................................................... 74 10.1 Minimize ...................................................................................................................................... 75 10.2 Single Point .................................................................................................................................. 76 10.3 Use External Charges.................................................................................................................... 76 5 10.4 Use Gasteiger Charges .................................................................................................................. 76 10.5 Normal Vibrational Modes............................................................................................................ 76 10.6 Mopac........................................................................................................................................... 76 10.7 Ampac .......................................................................................................................................... 77 10.8 Gaussian ....................................................................................................................................... 77 10.9 Gamess ......................................................................................................................................... 77 10.10 Orbitals ....................................................................................................................................... 78 10.11 Vibrations ................................................................................................................................... 78 10.12 GMMX ....................................................................................................................................... 78 10.13 Metropolis-MC ........................................................................................................................... 78 10.14 Vibrational Mode Search............................................................................................................. 78 10.15 Dynam ........................................................................................................................................ 79 10.16 Auto Dock .................................................................................................................................. 79 10.17 Manual Dock .............................................................................................................................. 80 10.18 Batch .......................................................................................................................................... 81 10.19 Rot_E.......................................................................................................................................... 81 10.20 Dihedral Driver ........................................................................................................................... 82 10.21 Relaxed Grid Search ................................................................................................................... 83 Chapter 11 Analyze Menu ........................................................................................................................ 85 11.1 Surface Area ................................................................................................................................. 85 11.2 Volume ......................................................................................................................................... 85 11.3 Connolly Surface .......................................................................................................................... 85 11.4 Compare ....................................................................................................................................... 85 11.5 Dihedral Map................................................................................................................................ 87 11.6 Movie ........................................................................................................................................... 87 11.7 Dot Map........................................................................................................................................ 87 11.8 MultiStructure............................................................................................................................... 88 11.9 Assign Symmetry.......................................................................................................................... 89 Chapter 12 Substr Menu ........................................................................................................................... 91 12.1 Read ............................................................................................................................................. 91 12.2 Create ........................................................................................................................................... 91 12.3 Move ............................................................................................................................................ 91 12.4 Connect ........................................................................................................................................ 92 12.5 Fuse .............................................................................................................................................. 92 12.6 Erase............................................................................................................................................. 92 12.7 Show Dummy ............................................................................................................................... 92 12.8 Don't Minimize ............................................................................................................................. 93 Chapter 13 Mark Menu............................................................................................................................. 95 13.1 H_Bonds....................................................................................................................................... 95 13.2 Pi Atoms....................................................................................................................................... 95 13.3 Metal Coordination ....................................................................................................................... 96 13.4 TS_Bond Orders ........................................................................................................................... 96 13.5 Fix_Distances ............................................................................................................................... 96 13.6 Fix Angle...................................................................................................................................... 97 13.7 Fix_Torsions................................................................................................................................. 97 13.8 Reset............................................................................................................................................. 97 Chapter 14 Options Menu......................................................................................................................... 99 14.1 Printout ......................................................................................................................................... 99 14.2 Dielc ............................................................................................................................................. 99 14.3 DPDP ........................................................................................................................................... 99 14.4 Minimizer ................................................................................................................................... 100 14.5 MMX_PI Calculation Options..................................................................................................... 100 14.6 Added Constants ......................................................................................................................... 101 14.7 Standard Constants...................................................................................................................... 101 14.8 Stereo ......................................................................................................................................... 101 14.9 Pluto ........................................................................................................................................... 101 6 14.10 Vdw Surface ............................................................................................................................. 102 14.11 Dot Surface ............................................................................................................................... 102 15 The MMX Force Field....................................................................................................................... 105 15.1 The MMX Force Field ................................................................................................................ 105 15.2 Minimization with PCMODEL (hints) ........................................................................................ 107 15.3 Transition State Atoms............................................................................................................... 108 15.4 Pi Calculations ............................................................................................................................ 109 15.4.1 Pi Atoms .............................................................................................................................. 109 15.4.2 Heat of Formation of Pi Systems .......................................................................................... 110 15.5 Transition Metals ........................................................................................................................ 111 Chapter 16 File Formats ........................................................................................................................ 114 16.1 PCM File Format ........................................................................................................................ 114 16.2 MMX Input Files ........................................................................................................................ 119 16.3 Mopac and Ampac Files.............................................................................................................. 135 16.4 X-RAY Files............................................................................................................................... 136 16.5 SDF and Mdl Mol Files............................................................................................................... 137 16.6 Chem3D and Tinker Files ........................................................................................................... 137 16.7 Cambridge Structural Database Files........................................................................................... 137 16.8 Alchemy and Sybyl Mol Files ..................................................................................................... 137 16.9 Gaussian Input and Output Files.................................................................................................. 137 16.10 Gamess Input and Output Files.................................................................................................. 137 16.11 ADF, PQS, Hondo and Turbomole Files ................................................................................... 137 16.12 Smiles Files .............................................................................................................................. 137 Chapter 17 Parameter Files..................................................................................................................... 138 17.1 Overview .................................................................................................................................... 138 17.2 Atom Types ................................................................................................................................ 139 17.3 Bonds ......................................................................................................................................... 139 17.4 Angles ........................................................................................................................................ 140 17.5 Stretch-Bend ............................................................................................................................... 141 17.6 Torsions...................................................................................................................................... 141 17.7 Van der Waals ............................................................................................................................ 142 17.8 Charge and Dipole ...................................................................................................................... 142 17.9 MM3 Specific ............................................................................................................................. 142 17.10 Pi Calculations .......................................................................................................................... 143 7 8 Chapter 1. Overview 1.1 Introduction PCMODEL is an interactive molecular modeling program for the study of organic and inorganic molecules. PCMODEL is simple to use and has a number of structure creation, display and energy minimization options. In this manual, we will discuss installation of the program, the features of the various menus, the different force fields supported by PCMODEL, and the formats of the various files that can be read and written. A short tutorial on structure building and manipulation is also included. A complete discussion of the methods of molecular mechanics is beyond the scope of this manual. General information about molecular mechanics can be found in the book "Molecular Mechanics", U. Burkert and N. L. Allinger, ACS Monograph Series, Number 175 and in "A Handbook of Computational Chemistry: A Practical Guide to Chemical Structure and Energy Calculations", by Tim Clark, J. Wiley and Sons, 1985. More current information can be found in "Journal of Computational Chemistry", edited by N. L. Allinger and the book series "Reviews in Computational Chemistry", edited by K. Lipkowitz and D. B. Boyd. 1.2 Changes in Version 7 Version 7 of PCMODEL introduces several major changes; the most important of which is the addition of support for other force fields. The current release supports the MM3 and MMFF94 force fields in addition to the MMX force field that was in earlier versions of PCMODEL. Planned for future releases is support for the Amber, Charmm and OPLS force fields. In order to support additional force fields we have rewritten the entire force field section of the code, added new minimizers and changed the format of the parameter files. Version 7 includes both a first derivative minimizer and also a full-matrix second-derivative minimizer. 1.3 Changes in Version 7.5 Version 7.5 of PCMODEL introduces several additional changes. The current release now supports the AMBER force field. Additional items have been added to the Menu Bar. Some items under the View and Compute options have been moved to a new Analyze menu item. The View options now include the ability to change the screen background color, to view structures in red and green stereo, to have a small top view of the structure and to display a dipole vector. The Analyze menu options have added the ability to display the molecular symmetry, and view/analyze multiple structure files. With the multiple structure option one may view in sequential or random order a multiple structure file. One may also do a query on a set of structures, extract structures which match a query or do a global comparison of all structures in a file. The Compute menu option has added the ability to do normal vibration mode calculations and the ability to do conformational searches using low-mode vibrations. The use of solvents has also been improved. 1.40 Changes in Version 8.0 Version 8.0 of PCMODEL includes support for the Oplsaa force field, reading Gaussian Formatted checkpoint files, reading and writing Hondo files. In the Compute Menu there are options to use charges read from a structure file or Gasteiger charges rather than the default force field charges. There is a Manual Docking option, and there are more options for running Batch calculations. The ability to change the atom colors and the background colors has been added to the Options Menu 1.41 Changes in Version 8.5 Version 8.5 of PCMODEL adds support for the PQS, ADF and Turbomol quantum chemistry programs. In the File Menu there is now an option to save Movie files, under the Save Graphics option there is support for PovRay files. In the Edit Menu there is support for reading the Pcmod.Err and Pcmod.Out files so that errors due to missing constants can be checked without exiting PCMODEL. In the View Menu there is an option to show the Backbone of a polypeptide and in the Compute Menu an option for a Relaxed Grid Search. In the Analyze Menu there is an option for calculating surface areas and volumes using the Connolly algorithms, and there is further support for analyzing multiple structure files. The Templates Menu now contains a set of Heterocycles and the Substr Menu now has a Fuse option for fusing two rings. 1.42 Changes in Version 9.0 Version 9.0 of PCMODEL has a completely rewritten graphics engine based on OpenGL. This greatly improves rendering of screen images. Highlighting of atoms or bonds is now visible in Stick Figure, Ball and Stick and CPK views. The format of the ouput window has been changed. The Movie option now reads Gaussian 03 formatted checkpoint files for IRC calculations. Two dimensional SDF files, such as those output by Isis Draw, that contain stereochemical information can now be converted to three dimensional structures. In the Edit Menu there is now an option to Set the atom type of a specific atom, and also an option to List all the atom types in the current force field. In the Options menu the user can now reset the paths which point to external programs such as Gaussian, Gamess or Mopac. 1.5 History PCMODEL is derived from several sources. The graphical user interface originally came from MODEL, written by C. Still. It has been extensively modified for PCMODEL for WindowsTM. MODEL was ported to the IBM-PC and renamed PCMODEL by M. Mark Midland, University of California, Riverside, J.J. Gajewski of Indiana University, Kosta Steliou of Boston University and K.E. Gilbert of Serena Software. K. E. Gilbert, J. J. Gajewski and T.W. Kreek of Indiana University then ported PCMODEL to the Macintosh, Silicon Graphics and Sun workstations. K.E. Gilbert wrote the current version of PCMODEL for Windows, the Apple Macintosh, Unix and Linux. The default force field used in PCMODEL is called MMX and is derived from MM2 (QCPE-395, 1977) force field of N. L. Allinger, with the pi-VESCF routines taken from MMP1 10 (QCPE-318), also by N. L. Allinger. J. McKelvey of Kodak modified the pi-VESCF routines for open shell species, while J. J. Gajewski did improvements to the heat of formation calculations. MMX increased the number of atom types for the MM2 force field, added the ability to handle transition metals and transition states, and increased the number of parameters included in the database. J. J. Gajewski and K. E. Gilbert made these changes. Algorithms to compute surface areas and volumes using a Monte Carlo method were provided by Professor William Herndon of the University of Texas at El Paso. 11 1.6 The PCMODEL Window PCMODEL uses a standard window in all versions of the program. The main window in the WindowsTM version is shown below. A menu bar appears at the top of the screen, with 10 options - FILE, EDIT, VIEW, COMPUTE, ANALYZE SUBSTR, TEMPLATES, MARK, OPTIONS, FORCE FIELD and HELP. The commands under each of these headings are described in detail in later chapters. A second bar of drawing tools appears along the right hand edge of the screen (this is referred to as the TOOLS menu or Drawtools menu) The Drawtools menu may be moved. At the bottom of the screen is a status bar, which indicates the status of various options. 12 1.7 Definitions Within this manual, the terms window and screen will be used interchangeably to refer to the main graphics window in which PCMODEL is running. The term attached atom refers to an atom with only one connection, such as hydrogen attached to a carbon. A connected atom is one that is connected to the given atom and may include an attached atom. Pointing, clicking, hitting or pressing a button all refer to a single click of the left mouse button over the word, button, atom or bond. A substructure is a collection of atoms that may or may not be connected, that have a common value among their substructure numbers and an associated name. Substructures can be moved, rotated, connected, hidden, minimized independently, and docked to one another or to a main structure. When written with a PCM file format, substructure information is maintained, so substructures can be stored. A single atom may belong to more than one substructure. When a substructure is connected to another structure, a bond is formed but the substructure information is maintained. Thus, a substructure can be part of a contiguous structure, and when the structure is moved or rotated the joining bond can be stretched abnormally. Remember that, when connecting substructures, the substructure that is chosen many not be the entire connected structure, thus leading to the stretch of one bond in order to form the connected bond. 1.8 Closing Notes This manual describes only a few of the possible chemical structures that we can study with PCMODEL. We have tried to do the very best job of representing chemistry with a computer model. No doubt there are many problems still remaining and many faults with our models. If you find problems, or think the calculations are incorrect, please let us know. We are always trying to improve the chemistry of PCMODEL and since we are few and the problems are many, your help is always appreciated. We can be reached at: Phone (812)-333-0823 FAX (812)-332-0877 Email [email protected] WWW http://www.serenasoft.com/ Mail Serena Software Box 3076 Bloomington, IN 47402-3076 13 14 Chapter 2. Installation 2.1 Windows Installation This manual assumes a basic working knowledge of the operation of your computer system, and the WindowsTM software. If there are things mentioned which are not clear, consult your computer's user or system administration help procedures or manuals. PCMODEL for WindowsΤΜ is shipped as a series of files on a CD. Installation from a CD You should first create a directory on your hard disk to contain the PCMODEL program. Then you will need to copy all the files from the CD into the new folder on the hard disk. The list of files given below will now be on the hard disk and ready to use. Do not drag the entire CD onto your hard drive, if you do Windows will mark the resulting folder as a “read only” folder and Pcmodel will not be able to write backup files and output files into this folder. This will result in Pcmodel crashing with “write protect”errors. Pcm9.exe mmxconst.prm mm3.prm mmff94.prm amber.prm oplsaa.prm aa.sst nu.sst su.sst rings.sst hetero.sst templt.sst fg.sst orgmet.sst executable copy of PCMODEL text file containing specific constants used by PCMODEL file containing MM3 constants used by PCMODEL file containing MMFF94 parameters file containing AMBER parameters file containing Oplsaa parameters Substructure template files " " " " " " " You may now return to WindowsΤΜ and use the TaskbarΤΜ setup from the Setting option in the Start Menu to install the PCMODEL icon. In the Taskbar properties dialog box choose the Start Menu Programs and then choose Add to add a new item to the Task Bar. Use the Browse option to search for pcm9.exe, then select the program group for the icon or create a new program group. 2.2 Macintosh Installation PCMODEL for the Macintosh is shipped as the fully expanded program on a CD. Create a new folder on your hard drive and drag the files from the CD onto the hard drive. The files are listed above with the only change being the in the program name: Pcm9.app OS X version of PCMODEL If you drag the entire CD onto your hard drive OS X will mark the new folder as write protected and Pcmodel will crash when you try to minimize anything, so just copy the contents of the CD. Also, OS X treats the forward slash, ‘/’, as a special character (as does Unix and Linux) and you can not use it in folder names. If you do Pcmodel will not start. The constants files, *.prm, contain the parameters used in the calculations. These are text files that can be read and edited with a word processor to make parameter editing and addition easier. Please be certain to save these files as text only files when editing them with a word processor like Microsoft Word. If you save them as a standard Word document they will have formatting information embedded in the file and will not be read properly by PCMODEL. Using a simple, non-formatting text editor, such as Teach Text, is recommended. When Pcmodel starts it will locate the folder it resides in and will also get the current working folder from OSX and it will write the output and backup files into the current working folder. Thus it is possible to install Pcmodel into a write-protected area and to have multiple users accessing the program. The output for each user will usually be placed in the users document folder, ie /Users/usename/documents. 2.3 Linux Installation PCMODEL for Linux or Unix is shipped in as a compressed tar archive, pcm9_linux.tar.gz. Copy this file to the hard drive on your computer, unzip it using gunzip and then extract the files from the tar archive. The standard commands would be (assuming you are logged into your home directory): Cp /mnt/cdrom/pcm9_linux.tar.gz . Gunzip pcm9_linux.tar Tar xvf pcm9_linux.tar PCMODEL uses X and OpenMotif on Linux, however, the executables are statically linked and you will need to have Motif or Lesstif installed only if you will be recompiling the source code. The latest version of Lesstif can be obtained from www.lesstif.org and OpenMotif from www.openmotif.org .Pcmodel now uses OpenGL for the graphics engine and uses the current screen depth automatically. The source code is included along with a Makefile. Please consult your Linux documentation if you have not installed all the libraries necessary. Pcmodel can use the environment variable PCM_DIR to locate the parameter and template files. If the PCM_DIR variable is not defined Pcmodel will look in the current working directory for these files. The output and backup files will be written to the current working directory. The Linux version of PCMODEL has been tested with RedHat (up to version 7), SuSE (v 9) and Mandrake (v9). Other versions of Linux and other flavors of Unix can be supported by recompiling the source code. We have recompiled the current source code on SGI and HPUX computers with only one modification of the source. You will also need to edit the Makefile included with the source code to use these systems as appropriate for your system. 16 2.4 General Comments You are now ready to run PCMODEL by double clicking on the PCMODEL icon. PCMODEL normally only uses sixteen colors for drawing structures, however if you want good CPK surfaces you should set your monitors control to Millions of colors (if possible), otherwise use 256 colors. This will have no effect on normal operation of PCMODEL. There are some fundamental hardware differences between a PC, a Macintosh and Linux, such as the Macintosh having only a one button mouse while the PC normally uses a three button mouse. Where this is important we will make a comment in the documentation, but we have tried to make the three versions as similar as we can so functions should look and feel the same in the Windows, Macintosh and Linux versions. 17 18 Chapter 3. Quick Summary of PCMODEL Menu Bar Functions File Menu Open Save SaveGraphic SaveMovie Print Read pcmod.bak Exit Edit Menu Draw Erase Structure Name Hide Hydrogens Epimer Enantiomer Remove LP Retype Set Atom Type List Atom Type Read Pcmod.Out Read Pcmod.Err Copy_To_Clipboard Reads a file from disk. Saves a file to disk Saves a graphics image to a disk file Saves a Movie to a disk file Prints the current structure and energy windows Read pcmod.bak file Exits PCMODEL Recovers the TOOLS menu Erases all structures Edit or enter name of current structure Make the hydrogens in a structure invisible but still present Epimerizes the selected atom by interchanging the two selected attachments. Reflects the structure through a specified axis Remove lone pairs from a structure. Forces PCMODEL to reassign atom types. Set the atom type of the selected atom and prevent retyping this atom. List the atom types in the current force field. Read Pcmod.Out file using simple text editor Read Pcmod.Err file using simple text editor when missing constants error message is shown. Copies an image of the structure window to the clipboard. Orient_XY Orient_XZ Orient_YZ Orients the selected three atoms in the XY Plane with the first atom at the origin the second atom along the axis and the third atom in the plane. Build Solvent Box/Solvate Build a box of solvent molecules or solvate the current structure. Build Periodic Box Build a box of the current structure. View Menu Control Panel Labels Brings up a dialog box to scale, translate and rotate structures in the structure window. Dialog box to change the structure labels 19 Mono/Stereo Stick Figure Ball and Stick Pluto Tubular Bonds CPK Surface Dot Surface Ribbon BackBone RedGreen Stereo Top View Dipole Vector Compute Menu Minimize Single Point Use External Charges Use Gasteiger Charges Use GB/SA Model Normal Vibrational Modes Mopac Ampac Gaussian Gamess Toggles between mono and stereo display Display all structures as stick figures. Display all structures as ball and stick. Display all structures as Pluto type ball and stick. Display all structures as Tubes. Display all or selected structures with CPK surface. Display all or selected structures with dot surface. Ribbon diagram of peptide or nucleic acid backbone Display a Backbone picture of peptide. Sets view to red/green stereo Turns on top view of current structure Draws a dipole moment vector on current structure. Minimize the current structure(s). Calculate the energy of the current structure(s). Use charges read from Mopac or Ampac file Use charges generated by Gasteiger sigma model Use generalized Born salvation model Compute normal vibrational modes Runs the quantum chemistry program Mopac. Runs the quantum chemistry program Ampac Runs the quantum chemistry program Gaussian. Runs the quantum chemistry program Gamess. Orbitals Runs the Orbdraw program to view molecular orbitals and electron densities Vibrations Runs the Vibrate program to view normal vibrational modes GMMX Runs the conformational searching program on the current structure. Metropolis MC Runs conformational search using Monte Carlo algorithm Vibrational Mode Search Runs conformational searching using low frequency vibrational modes as search directions. Dynam Auto Dock Molecular Dynamics simulation. Simulated annealing search of lowest energy interaction between two structures. Manually move two structures to dock them Read a multiple structure file and minimize all structures. Rigid rotor evaluation of rotational energy barrier. Grid search with minimization evaluation of rotational energy barrier. Use Grid Search as starting point for Minimization but no fixed dihedrals Manual Dock Batch Rot_E Dihedral Driver Relaxed Grid Search Analyze Menu 20 Surface Area Volume Connolly Surface Compare Dihedral Map Calculate Surface area of molecule. Calculate Volume of molecule. Use Connolly algorithms for surface area and volume Compare different structures. Display the results of dihedral driver calculations. Movie Replay the structures contained in a multiple structure file. Currently supports PCM, MMX, Gaussian and Cambridge Structural Database file formats. Dot Map Multi Structure File Assign Sym Generate a dot map from a multi conformation file. Analyze a file containing multiple structures. Assign point group symmetry to current structure. Substr Menu Read Create Move Connect Fuse Erase Show Dummy Don't Minimize Templates Menu Rings Amino Acids Sugar Nucleosides Heterocycles OrganoMetallics Transition State Functional Groups Mark Menu H Bonds Pi Atoms Metal Coord TS_BondOrders Fix Distance Fix Angle Fix Torsions Equivalent Pi Atoms Read a structure file and label the structure as a substructure. Label the selected structure as a substructure Move the selected substructure. Connect two structures. Fuse two rings. Erase the selected substructure Displays dummy atoms in current structure. Mark the selected substructure so that it will not be minimized in a molecular mechanics calculation. Dialog box to read in selected ring systems. Dialog box to read in and connect Amino Acids. Dialog box to read in and connect Sugars. Dialog box to read in Nucleosides. Scrolling list of Heterocyclic Rings Dialog box to read in selected organometallic structures. Dialog box to read in selected transition state models. Dialog box to read in selected functional groups for connection to larger structure. Hydrogen Bonds Pi atoms. Set electron count, charge and coordination of metal atoms. Set the bond orders for transition state bonds. Fix a distance between any two atoms Fix an angle. Fix a dihedral angle Mark pi atoms to be made equivalent 21 Create Centroid Reset Options Menu Printout Dielc Input/Output Atom Types DPDP Minimizer MMX_Pi Calc Added Constants Standard Constants Stereo Pluto CPK Surface DOT Surface Change Background Color Change Atom Colors Reset Default Paths Edit PBC Create a centroid for five and six membered rings. Reset any of the above and also substructure membership. Sets the amount of output in PCMOD.OUT. Resets the dielectric constant. Define the atom types to be used in reading/writing structure file that uses atom types. Change between dipole-dipole and electrostatic calculations. Set options for the minimizers. Set options for Pi calculation Allows user defined constants Rereads the default MMX datafile Changes the direction of rotation of stereo display. Sets options for the Pluto Display. Sets the options for the VDW display. Sets the options for the DOT surface display. Change the default color of the Background Change the default colors of the Atoms. Reset the paths to external programs. Edit periodic boundary conditions Force Field MMX MM3* MMFF94 Amber Oplsaa Use the MMX force field. Use the MM3 force field Uses the MMFF94 force field. Uses the Amber 95 force field. Uses the Oplsaa force field. Help Menu About Help Current version of PCMODEL Start a browser to read the Pcmodel documentation. 22 Quick Summary of TOOLS Menu: Sel-Atm Sel-Bnd Draw Build Update H/AD Add_B In Out Del Move Rot-B Query PT Metals Rings AA Su Nu OrgMet TransSt Select atoms. Select bonds. Draw a carbon skeleton in either the plane of the screen or the plane of the first selected atom. Generate 3-D structure by replacing selected hydrogen with methyl group. Starting from ethane, any hydrogen selected will be replaced by methyl. Update the structure and redraw the screen. Add and delete hydrogens and lone pairs. Increment the bond order of the selected bond. Push an atom into plane of screen. Pull atom out of plane of the screen. Delete an atom or bond. Move an atom. Select Move, then atom, then new position. Rotate about the bond selected by four connect atoms. Query selected position, charge, POAV, distance, angle or dihedral. Works by first selecting Query, then selecting one, two, three or four atoms followed by blank space in drawing window. Queries removed by selecting Update button twice. Dialog box to choose atom type. Dialog box to choose metal atom type. Dialog box to read in selected ring systems. Dialog box to read in (and connect) Amino Acids. Dialog box to read in (and connect) Sugars. Dialog box to read in Nucleosides. Dialog box to read in OrganoMetallic structures Dialog box to read in transition state models. 23 24 Chapter 4. Tutorials PCMODEL is designed to be easy to use. In this chapter the basics of using the program, along with many of its options, will be covered through example. Before beginning the specific examples, there are some general points about structure entry to be considered. The screen is two dimensional. Initial input occurs at 0 on the z-axis. The screen itself is the xy-plane. Thus, a hexagon drawn to represent cyclohexane using the DRAW Command is initially flat. To obtain three-dimensional structures you need to move atoms behind or in front of the z plane with the IN and OUT commands on the TOOLS menu. Once some three-dimensional information is available, further structural input can be done by rotating the structure. If you pick an atom and draw a bond to a new atom, the new atom will lie parallel to the picked atom along the coordinate that is perpendicular to the screen. Complex structures are easier to build using the substructure ADD, ROTATE and MOVE commands. You can use the built-in substructure templates, or build a library of your own by creating structures and saving the minimized coordinates in an MMX or PCM file. Options are selected by pointing to the desired option and clicking (move the cursor until it is over the desired option and click the left mouse button). If the wrong option is chosen, simply choose the correct one and continue. Likewise, atoms are input or selected by pointing to the appropriate spot in the drawing box. When the cursor is over an atom the atom will be highlighted (a box will be drawn around the atom) so you may tell which atom is closest to the cursor. On the PC the right mouse button may always be used to rotate the current structure. Holding the right mouse button down and dragging the mouse will cause the structure to rotate. Moving the mouse to the left or right will rotate about the y-axis, while up and down movement rotates about the x-axis. Holding down the shift key while dragging the mouse will rotate the structure about the Z-axis. On the Macintosh simply hold down the mouse button and drag. More complete control of rotation, translation and scaling is had using the Control panel in the View Menu. The following examples will illustrate a few of the options available for structural input, minimization and display using PCMODEL. A few mistakes will be purposely made along the way to illustrate how they may be corrected. 4.1 Methylcyclohexane Structures are drawn on the screen in essentially the same way as they would be represented as 3-D structures on paper. For example, a hexagon could be drawn. Initially this would be in the XY plane with all Z coordinates equal to zero. Three-dimensional information could be entered by using IN to push one atom in to the screen and OUT to place the opposite atom in front of the screen. Alternatively, OUT could be used to place 3 alternating carbons in front of the screen to provide a chair shape. In this tutorial, however, we will begin by drawing a side-on view of the chair form. 4.1.1 Drawing the Structure 25 Begin by selecting the DRAW button on the TOOLS menu with the mouse. A dotted outline will indicate that you are in Draw mode. Move the cursor off the TOOLS menu and into the drawing box, somewhere in the upper right hand corner. (We will be drawing cyclohexane as in Figure 4.1.) Click the mouse button once then move the cursor down ~ 3 cm and left another 3 cm, and click again. A line indicating a bond between the first atom and the one just placed will be drawn. Continue drawing in this manner, placing atoms 3, 4 and 5. 1 2 3 5 6 4 Figure 4.1 Completed cyclohexane structure with atom numbers displayed. The atom numbers can be displayed on the screen by choosing LABELS from the VIEW menu, then clicking in the circle next to "atom numbers" and clicking on "okay". They can be removed by again choosing LABELS from the VIEW menu, then clicking in the circle next to "Hydrogens and Lone Pairs" At this point, we will purposely make a mistake, by connecting atom 2 to atom 5. To get back into the drawing mode, select DRAW from the TOOLS menu. Then, click on atom 5, then on atom 2. This will create a bond between atoms 2 and 5. (If the cursor is within about 1/4 inch or 0.5 cm or an atom, then that atom will be picked by the program instead of creating a new one.) To correct the mistake, move the cursor to the DEL button on the TOOLS menu and click on it. Now click on the middle of the bond between atoms 2 and 5 (the incorrect bond). The structure will be redrawn with the deleted bond removed. To continue drawing, again click on the DRAW button on the TOOLS menu, then click on atom 5 and continue to draw atom 6 and the bond back to atom 1. At this point the structure should resemble a chair cyclohexane as in Figure 4.1. However, remember that all the atoms are still in the plane of the screen, that is, no 3-D information has been included. To fix the structure, choose OUT from the TOOLS menu, and then click on atom 2 twice. Each click moves the atom 0.33 Å out of the plane of the screen. Next, point to atom 3 and click 2 times. Now select IN from the TOOLS menu and click on atom 5 twice and atom 6 once (another mistake which we will shortly correct). Rotation of the structure by dragging the mouse will reveal the changes in the structure. The initial view of the molecule is in the XY plane. The Z+ axis comes out towards the user. To view the structure from a different orientation, select CONTROL_PANEL from the VIEW menu. A new window entitled "Dials" will appear. Within this window will be continuous sliders that allow you to change the orientation of the structure. By clicking on the arrow at either end of a slider once, the view will move slightly. Holding down on one of the arrows will provide 26 continuous movement in that direction. Alternatively, you may click on the box in the middle of the slider bar, and drag it while holding down with the mouse button. This will also provide continuous movement of the view until the mouse button is released. The RESET_VIEW button will return the structure to its original orientation. If you rotate the structure in the Y direction, you can see how atoms 2 and 3 line up, but atoms 5 and 6 do not (because atom 6 was purposely moved only once). This could be corrected by returning to the original view, then using IN on atom 6 one more time. However, we will correct this using the MOVE command from the TOOLS menu. After selecting MOVE from the TOOLS menu, click on atom 6, then near atom 5 (the position to which atom 6 should be moved). The structure will be redrawn with the correction. Hydrogens may be automatically added by selecting the H/AD command from the TOOLS menu. However, once you have done this, there is no free valence at which to add the methyl group. This can be corrected in one of two ways. The first alternative is to delete the hydrogens by clicking on H/AD again, then select DRAW and click on atom 1 then on a blank space to the right of atom 1 to add the extra methyl group. (If the structure is too large, there will not be room on the screen to add the methyl group. If this is the case, use the SCALE option, accessed through the CONTROL_PANEL option of the VIEW menu, to shrink the structure to a more manageable size.) The structure would them be completed by re-selecting H/AD to add the hydrogens. A second alternative is to change the equatorial hydrogen into a carbon. Select PT (Periodic Table) from the Tools menu. Select C from the list of available atom types, and click on the equatorial hydrogen. Select H/AD to delete hydrogens (but the equatorial carbon will stay), then H/AD again to add hydrogens. The PERIODIC_TABLE window may be removed be selecting CANCEL (the last option in this window). This method of replacing specific hydrogens is very useful for controlling the stereochemistry when building large and complicated structures. A third alternative is to use the Build command from the Tools. In Build mode clicking on a hydrogen replaces that hydrogen with a carbon and then does a hydrogen delete/add sequence so the methyl group is added with only one click of the mouse. It is not important if the structure does not look perfect at this point. Only a crude approximation of the structure is needed for minimization. However, the closer to correct the structure is, the faster the minimization will proceed. Methyl groups pointing in to the middle of a cyclohexane ring will obviously cause problems. Also, if three carbons are attached to a central carbon such that all 4 are in a plane, the program will have difficulty in adding a hydrogen in the correct position. You can check for such errors by using the rotation and translation sliders in the DIALS box to get different views of the molecule. Use IN, OUT and MOVE from the TOOLS menu to correct these problems. Before starting a minimization, it is a good idea to store the structure with a descriptive filename. Select SAVE from the FILE menu. Select the appropriate file type from the list provided by clicking on it with the left mouse button. (The default file type of PCM is preferable.) The "File Name:" box will change to indicate the default extension for that type of file. The "*" in the file name should be changed to a descriptive name for this structure, for example, etcyclo. The path indicating where the file is to be saved may also be changed at this time. When the correct path and filename have been entered, click on "OK" or press return on the keyboard to save the structure in the indicated location. At the beginning, every five iterations during, and at the end of the minimization process a backup file of the structure, called PCMOD.BAK will be written (the format is PCM). If anything should go wrong or should you need to stop the program, you may restart the minimization by reading in this file and continuing from the last saved point. 27 4.1.2 Building the Structure A structure may also be constructed by using the BUILD command of the DRAW TOOLS. Begin by selecting BUILD. An ethane will appear (Figure 4.2). Click on the upper right hydrogen to produce propane as shown in Figure 4.3. Next click on hydrogen 10 to provide butane as shown in Figure 4.4. It may be easier to see the 3-dimensional nature of the structure if you turn on Tubular Bonds from the View Menu as in Figure 4.5. However it is usually easier to click on atoms using the stick figure. You can rotate the structure at any time by holding down the mouse button (right button on the PC) and dragging. Figure 4.2. Figure 4.3 Figure 4.4 Continue the build by clicking on the next hydrogen in the sequence to obtain Figure 4.6 and then to obtain Figure 4.7. Again it may be helpful to turn on Tubular Bonds to see the 3-d structure. 28 Figure 4.5 Figure 4.6 Figure 4.7 Complete the ring by removing the hydrogens (H/AD) and then use Draw to create a bond between carbon 1 and 6. It does not matter if you draw the bond first or remove hydrogens first. You will arrive at Figure 8 either way. Figure 4.8 Figure 4.9. Figure 4.10 Complete the structure by adding the hydrogens (H/AD) to give Figure 4.9 and then using Build to add the methyl group (Figure 4.10). The easiest method for constructing methylcyclohexane is to read C6 from the RINGS template of the Draw Tools or under Template on the Menu Bar then add the methyl group using BUILD. 4.1.3 Minimizing and Adjusting the Structure The structure may now be minimized. Select MINIMIZE from the ANALYZE menu, and the calculation will automatically start. Once the minimization process has started, pointing to the Stop Job button may stop it. The cursor will change into an hourglass shape while the minimization is in progress, and will return to the arrow shape when it is completed. The final energy should be around 6.89 kcal. Save this structure, as it will be used later. We now want to compare the energy of the equatorial isomer to that of the axial isomer. We could start from scratch by clearing the current structure by selecting ERASE from the DRAW menu, and drawing in a new chair cyclohexane with an axial methyl group. However, it is usually simpler to modify the present structure. This can be done in several ways. Some choices are: 29 Use MOVE: Select H/AD to remove the hydrogens. Then select MOVE from the TOOLS menu, and click on the equatorial carbon. Next point to a new position above atom 1 where the axial group is to be located. Use H/AD again to add the hydrogens back on to the structure. Check that you have in fact obtained the axial isomer. If not, remove the hydrogens again and move the carbon atom further. Use DEL and the Periodic Table: Bring up the Periodic Table by selecting PT from the TOOLS menu. Choose the C atom, and click on the axial hydrogen to change it into a carbon. Then select DEL from the TOOLS menu and click on the carbon of the equatorial methyl group. It, along with the attached hydrogens, will be automatically deleted. Then click on H/AD twice to remove then replace the hydrogen atoms. Use DEL and BUILD: Select DEL from the TOOLS menu and click on the carbon of the equatorial methyl group. It, along with the attached hydrogens, will be automatically deleted. Then select BUILD and click on the axial hydrogen. Use EPIMER: Click on Sel-Atm on the TOOLS menu. Then click on carbon 1, then to the axial hydrogen and equatorial carbon. Small filled circles will indicate that the atoms have indeed been selected. If hydrogens obscure any of the atoms, use the DIALS box to rotate the structure to a better orientation, or SCALE it up to zoom in on the area of interest. Then select EPIMER from the EDIT menu, and the two attached groups will be switched. Now select MINIMIZE from the ANALYZE menu to find the energy of this structure. It should be about 8.67 kcal or 1.78 kcal higher than the equatorial isomer. Save this file with a different filename from that used for the equatorial isomer. 4.2 Trans-Decalin We will next illustrate how to build up a simple structure by converting axial methyl cyclohexane into 1-methyl- trans-decalin. Begin by reading in the minimized axial methyl cyclohexane structure previously saved by choosing OPEN from the FILE menu. Use H/AD to remove the hydrogens. Turn on atom numbering (LABELS under VIEW menu), bring up the DIALS box by choosing CONTROL_PANEL from the VIEW menu, and rotate the structure along the X-axis until it has an orientation similar to that in Figure 4.11. Using DRAW from the TOOLS menu, click on atom 1, then continue to place atoms 8, 9, 10 and 11, and the final bond back to atom 2. 30 10 9 11 8 7 2 3 1 6 4 5 Figure 4.11 Completed 1-methyl-trans-decalin structure with atom numbers displayed. Carbons 8 through 11 will have the same Z coordinate as atom 1, the last atom selected prior to drawing them. If we had chosen atom 2 as the starting point, then carbons 8 through 11 would have the same Z coordinate as atom 2. Use OUT to push atom 9 out 2 clicks, and IN to move atoms 10 and 11 each in 4 clicks. Use the rotation and translation sliders to check placement of the atoms and MOVE to correct any mistakes. Add the hydrogens back with H/AD and proceed with the minimization. 4.3 Special Options 4.3.1 Compare The COMPARE option is used to calculate the differences in two structures and to produce an overlaid view of two structures. Begin with axial methyl cyclohexane as the active structure. Select COMPARE from the VIEW menu. Select NEXT_STRUCTURE from the COMPARE menu, and enter the name of the equatorial cyclohexane structure. We will want to see how the axial and equatorial atoms change positions if the remainder of the ring is held constant. Use the Sel-Atm button from the TOOLS menu to mark carbons 3,4 and 5 on the left (axial) isomer, then carbons 3,4 and 5 on the right (equatorial) isomer. The comparison will pair the first atom selected on the first structure with the first atom selected in the second structure, etcetera, so it is important to select the atoms in the same order on the two structures. Once the atoms have been selected, choose CALCULATE from the COMPARE window. PCMODEL will now find the best least squares fit for these three atoms, and will give the rms differences between all corresponding atoms in the Compare Output window, and the structures will be redrawn overlapped, with red lines connecting the atoms that are being compared. If the structures overlap well, the red lines may not be visible. The structures may be rotated in mono or stereo to get a better view of the comparison. Select MOVE from the SUBSTR menu, and choose the substructure "untitled". Use the DIALS box to translate this substructure away from the other one. A new set of atoms for comparison can now be marked on each substructure (using the Sel-Atm option), and the calculation re-done. Click on CANCEL to dismiss the COMPARE window. 31 4.3.2 Rotational Energy Barriers PCMODEL can calculate rotational barriers using the DIHEDRAL_DRIVER option in the ANALYZE menu. However, there is a quick way to explore rotational minima using ROT_E from the ANALYZE option. Read in the equatorial methyl cyclohexane structure and convert one of the methyl hydrogens to a carbon using the BUILD option from the Draw Tools menu. After minimization, we will explore the rotational minima of the ethyl group. We will need to Sel-Atm carbon 1 and the first carbon of the attached methyl group (carbon 7). If hydrogens obscure these, rotate the structure until they are not hidden. Choose Sel-Atm from the tools menu, and click on the carbon of the ring where the ethyl group is attached and the first connected carbon atom. One may also use Sel-Bnd and click on the bond to be rotated. Then select ROT_E from the ANALYZE menu. Enter an increment of 10 and an extent of 360. Click on okay (or hit return). The program will then produce a plot and of energy vs. angle (this may take a few seconds to appear) similar to that shown. The energy scale is relative to the energy of the starting conformation and the angles are in degrees. The plot can be printed. To return to the structure window: In the Windows version pull down the File menu and choose Exit (the plot window has it's own menu bar and under the File menu there will be two choices, Print and Exit); In the Macintosh version choose Stick Figure from the View Menu. 4.4 Benzene and a Pi Calculation Select DRAW from the TOOLS menu and draw a hexagon. Next select ADD_B from the TOOLS menu to change every other bond in the ring to a double bond, by clicking in the middle of the bonds. Finally, use H/AD to add the hydrogens to create benzene. Although the structure now looks like benzene, it is not ready to be minimized because PCMODEL does not have any information about the pi system. Choose PIATOMS from the MARK menu, and the structure will be redrawn with small ~ symbols near each of the pi atoms. (PCMODEL automatically determines which atoms are pi atoms, once it has been told to look for them.) Minimize the molecule using MINIMIZE from the ANALYZE menu, then save it to disk using the SAVE command from the FILE menu. 4.5 Biphenyl and a Pi Calculation Begin with the benzene structure studied above as the active structure. Select READ from the SUBSTR menu, and read the benzene file back into the program. There will now be 2 benzene rings on the screen, side by side and several inches apart. Sel-Atm one hydrogen from each substructure, then choose CONNECT from the SUBSTR menu. The screen will be redrawn with the two hydrogens removed and a carbon-carbon bond in their place. Use Sel-Atm from the 32 TOOLS menu to highlight 4 carbons involved in the biphenyl dihedral, then select ROTATE_BOND from the TOOLS menu. Change the dihedral angle to plus or minus 5 degrees, then click on EXIT to return to the main window. Finally, select PIATOMS from the MARK menu since the atoms in the substructure may not be labeled as pi atoms at this time. Now minimize the system by choosing MINIMIZE from the ANALYZE menu. This time all the pi atoms will not lie in one plane. The structure should minimize to a dihedral angle of about 39 degrees with a shallow potential energy surface. 4.6 Ferrocene - Using Metals and Coordination The sandwich complex of iron and two cyclopentadiene rings can easily be modeled with PCMODEL. There are two ways to represent the cyclopentadiene rings: as aromatic rings with two double bonds and a carbon anion, or as a ring of aromatic carbons. Since the first option would require a pi calculation, the second option will be used. This atom type is designed to reproduce the bond lengths and angles of aromatic rings without requiring a special pi calculation. To begin, draw a five-membered ring. Double bonds may be added, but this is not necessary when the aromatic carbon type is used. Use the PT (Periodic Table) option from the TOOLS menu and replace all the ring atoms with atom type Ca (aromatic Carbon). Use H/AD to add hydrogens, then rotate the ring onto its side using the DIALS box (accessed via the CONTROL_PANEL option on the VIEW menu). Save the ring to a file, then read it back in as a new substructure using the READ option in the SUBSTR menu. If the two rings are too close together, Sel-Atm an atom in one and use SUBSTR MOVE to separate them. Select DRAW and place an atom between the two rings. To make this the iron atom select METALS, click on Fe and click on the isolated atom. Select UPDATE to clean up the structure. There should only be one hydrogen on each of the aromatic carbons, whether or not you have drawn in the double bonds in the cyclopentadiene rings. At this time PCMODEL does not know anything about the interaction of the cyclopentadiene rings with the iron atom. Use Sel-Atm to mark the iron atom and all 10 of the Ca atoms, then select METAL_COORD from the MARK menu. A dialog box will appear asking for information about the metal. Since this is an 18 electron complex select "saturated_18_e" for the electron count. Clicking on OK causes the screen to be redrawn with the metal coordination bonds shown in red. The structure can now be minimized. If the structure had been minimized without coordinating the iron to the rings, the iron atom would not have been bonded to anything and would have wandered out of the picture. 4.7 The Methanol dimer - Hydrogen Bonding and Docking This calculation will demonstrate the hydrogen bonding and docking capabilities of PCMODEL. To begin, draw and minimizing methanol. Select DRAW from the TOOLS menu and draw a 3-carbon skeleton. Next select PT and change the central atom to an oxygen (O) and one of the terminal carbons to a hydrogen (H). Now use H/AD to add the remaining hydrogens and lone pairs. If you repeat the H/AD command you will note that the hydroxyl hydrogen is not removed. Hydrogens attached to heteroatoms are not removed by H/AD and must be removed explicitly using the DEL command. (This is to ensure that particular hydrogen bonding orientations drawn by the user will not be disturbed by the normal H/AD function.) Minimize this structure 33 (MINIMIZE on the ANALYZE menu) and then save it in to file (SAVE under the FILE menu). Since there are no other heteroatoms present, hydrogen bonding was not important during this step. Next, read the methanol structure back in as a substructure using the READ command under the SUBST menu. A red line will appear between one lone pair and one hydroxyl hydrogen, indicating a potential hydrogen bond. Use the MOVE command under SUBST to move the second methanol molecule around so that the O-H-O system is linear, and is within bonding distance. (By default Hydrogen bonding is now turned on, use the REST option in the Mark Menu to turn it off). MINIMIZE (ANALYZE menu) the dimer. If the linear dimer is obtained, the energy should be -3 to -4 kcal. Next select DOCK from the ANALYZE menu to begin a simulated annealing calculation. The default settings are adequate for this system. Click on OK, and then enter a filename to store the results of the calculation. If the calculation is successful, the dimer energy will be between -4 and -5 kcal, and a linear hydrogen bond will be present. The calculation may be stopped at any point by hitting the ESC key. 4.8 Substructures - Creation and Manipulation In this example, we will create, move, rotate, hide and reset substructures. First, sketch two separate structures - a hexane and a pentane. To make the pentane into a substructure, choose SelAtm from the TOOLS menu and click on any atom in pentane. Select CREATE from the SUBST menu. A dialog box will appear asking for the name of this substructure, type "pentane" and select OK or hit return. Select LABELS from the VIEW menu and click on "Substructure Numbers". The atoms will now be labeled with numbers, according to the substructure to which they belong. Select MOVE from the SUBST menu, and the DIALS box will appear. Since an atom in the pentane substructure was still selected when SUBSTR MOVE was selected, the DIALS box will only move the pentane substructure. Click on EXIT to dismiss the DIALS box, then click on Sel-Atm on the TOOLS menu to de-select all atoms. Now select MOVE from the SUBSTR menu, and a dialog box will appear with a list of all currently defined substructures. Select a substructure from this list, and a new DIALS box will appear which will move only that substructure. To move a different substructure select click on one atom in a different substructure. As long as no other Draw Tools options have been used, the Sel-Atm option will still be active. This substructure now becomes the active structure and will be translated or rotated by the DIALS box. Now click on H/AD to add the hydrogen atoms. Use Sel-Atm to mark one hydrogen in each substructure, and select CONNECT from the SUBSTR menu. A bond connecting the two substructures will replace the hydrogens. Select MOVE from the SUBSTR menu, translate one structure, and notice that the central bond of the hexane is stretched. This will be the case whenever two separate substructures, which are directly bonded, are moved. Choose HIDE from the SUBST menu, if no atoms are selected a substructure list window will appear again. However, each substructure will have a lowercase "v" next to it, indicating that it is currently visible on the screen. Select pentane and say okay. The pentane structure will disappear from the display. Select HIDE from the SUBST menu again, and this time pentane will have an "i" next to it, indicating that it is invisible. Select pentane again and click on OK, and pentane will re-appear on the screen. Select ERASE from the SUBSTR menu, and select "Str 0" from the list. Note that the entire complex is erased. This is because pentane is still part of "Str 0", the initial structure, as well as being its own substructure ("pentane"). 34 4.8.1 Building Polystryene using Dummy Atoms Read in benzene from the Rings Templates and then select BUILD from the DrawTools. Select one of the hydrogen atoms on the ring to replace it with a methyl group. Next select one of the hydrogens of the methyl group and you should now have ethyl benzene. Minimize the structure to obtain a reasonable geometry. Bring up the Periodic Table from the DrawTools menu and select the dummy atom type, DU, from the dialog box. Next point to one of the hydrogens of the CH2 group and then the hydrogen anti to the first hydrogen on the CH3 group. Do an HAD sequence and notice that the hydrogens that were converted to dummy atoms are not removed by the hydrogen delete. Once the hydrogens are readded do a Minimization. Next , using SUBSTR READ, read in the pcmod.bak file. Highlight the Dummy atoms by using the Show Dummy command from the SUBSTR menu. There should be four dummy atoms showing on the screen. Next select the Connect command from the SUBSTR menu. This will bring up the Connect dialog box with the dummy atoms boxes filled. Selecting Connect will connect the two structures from the second dummy atom of structure 1 to the first dummy atom of structure 2. Selecting Next Structure brings up a File Open dialog box and a new structure can be read. Reread pcmod.bak and note that the Substructure Connect dialog box will be updated with new atom numbers for the dummy atoms. Selecting Connect adds the new structure to the old structure. Repetition of this procedure makes it easy to build oliogmers. You are not limited to single monomers since any structure can be read using the Next Structure button. As long as the new structure has two atoms marked as Dummy Atoms, the substructure connect function will work. 4.9 Diels-Alder Transition State To model the Diels-Alder transition state for the reaction of butadiene and ethylene, begin by drawing a hexagon of atoms (a flat cyclohexane). Use PT from the TOOLS menu to replace atoms 1 and 2 by C* and atoms 3 and 4 by C# and atoms 5 and 6 by C•. Use H/AD to add hydrogens and select MINIMIZE from the ANALYZE menu to optimize the structure. A dialog box will appear inquiring about what bond orders to use. The C*-C* bond represents a sigma bond being formed between one terminus of butadiene and one terminus of ethylene. Enter 0.3 for this bond order. The C#-C# bond represents the other sigma bond being formed. Enter 0.3 for this bond also, and then click on OK. This will start the minimization. The resulting structure should be very similar to that calculated by Houk et al. (Houk, K. N., Paddon-Row, M. N., Rondan, N. G., Wu, Y. D., Brown, F. K., Spellmaeyer, D. C., Metz, J. T., Li, Y., and Loncharich, R. J. Science, 1986, 231, 1108 and references therein.) 35 It should be noted that the bond length between the two C• carbons is 1.4 Å. (You can check this by selecting QUERY from the TOOLS menu, then clicking on each of the C atoms, then on a blank space on the screen. The distance between the two atoms will be displayed on the screen. To remove the distance from the screen, click on UPDATE twice.) If a normal double bond were drawn between these two atoms, the resulting minimized structure would have a 1.34 Å bond between these two carbons, which will ultimately give a double bond in the product. If other bond orders are chosen, the distances between the C* or C# carbon pairs will respond, as will the 1,3 angles at C* and C#. The calculated MMX energy is the potential energy of the system relative to the potential functions for the transition state, NOT relative to the ground state. As usual, the potential energy of a minimized structure can only be compared to a conformational isomer or a diastereomer. The potential energy of a transition state with one set of bond orders might be compared to the potential energy of another transition state with different bond orders, but only the difference in steric energy can be determined, not the actual free energy difference between the two structures. That is, the electronic energy difference is not considered in the MMX calculation. See the chapter on the MMX force field for more information. 36 37 Chapter 5. Drawing Tools The palette of drawing tools appears at the left-hand side of the drawing window when PCMODEL program is started. The palette can be moved anywhere on the screen by dragging on the "Tools" title. The window can be closed by clicking on the CANCEL button at the very bottom, and recalled by selecting DRAW from the EDIT menu. 5.1.1 Select Atom This option allows certain atoms to be selected for action by future commands. As many atoms as desired can be selected. To clear all selected atoms, click again on the SELATM button 5.1.2 Select Bond This option allows bonds to be selected for action by future commands. As many bonds as desired can be selected. To clear all selected bonds, click again on the SELBND button 5.2 Draw This command enables the drawing mode. To create a new structure, select DRAW then move the cursor to the desired location and click the left mouse button. If the cursor is then moved to a new location and the left mouse button is clicked again, a line will be drawn, indicating a bond between the previous atom and the new one just placed. If the cursor is moved to a new location and the left button is clicked again, a third atom will be created and bonded to the second atom. Note that all atoms are added in the plane of the screen. To close a ring, place the cursor on an existing atom and click the button. The cursor must be within about 1/4 inch of an atom to draw a bond to that atom instead of creating a new one. A small box will appear around the atom when the cursor is close enough. To start drawing from an existing atom without adding a new bond to that atom, click on DRAW again, place the cursor on the old atom, click and continue drawing as before. New atoms will be added in the same plane as the last atom picked. To start drawing from a new location, click on the DRAW button again then move to the new location and click the mouse. A small dot will appear indicating a new atom. Clicking on DRAW, then selecting first one end of the double bond, then selecting the other end may create double and triple bonds. Conventional double lines will be used when the structure is redrawn. Alternatively, the ADD_B option can be used (see below). If there are many multiple bonds, this is the easier method to use. 5.3 Build This option allows for rapid building of 3-D structures. After selecting BUILD, click on any hydrogen and it will be replaced with a methyl group. This option allows PCMODEL to provide the 3-D information required to build the structure, as opposed to the DRAW option, where all atoms are added in the plane of the atom to which they are connected. (Or, in the plane of the screen, in the case of unattached atoms.) The structure may be rotated and viewed with tubular bonds to get a better 3-D view of the molecule. The Stick Figure view is best for selecting atoms. When building rings the ring closure bond can be generated by selecting the two atoms and then Add_B. 5.4 Update This option redraws the screen, and updates the structure with any changes since it was last drawn. It clears any Query information. 5.5 H/AD This command will automatically add or delete hydrogens and lone pairs. The structure will be redrawn with the appropriate structure. Hydrogens and lone pairs attached directly to metals will not be removed. Hydrogens attached to oxygen and nitrogen are not removed to preserve the orientation of hydrogen bonds. Note that removal of hydrogens followed by re-addition will not necessarily return you to the original structure. Hydrogens are added according to a geometric prescription. To remove hydrogens for viewing or comparison purposes only, use the H/OO command (see below). 5.6 Add_B This command increments the value of the selected bond by one (single to double to triple). After selecting ADD_B, click in the center of the bond to be incremented. An X will appear over the bond when you are close enough. The structure will be redrawn with the conventional double or triple line representation. If there are two atoms selected then Add_B will make a bond between the selected atoms. This is useful for closing rings generated by Build. 5.7 In This command pushes selected atoms behind the plane of the screen, by approximately 0.33 Å. Each time an atom is clicked on it will be pushed in an addition increment. 5.8 Out This command pulls selected atoms out of the plane of the screen, by approximately 0.33 Å. Each time an atom is clicked on it will be pulled out an addition increment. 39 5.9 Del This command DELetes an atom or bond. After selecting DEL, click once on each atom or bond to be deleted and the structure will be redrawn with the atom or bond deleted. If an atom is deleted, all bonds to that atom are deleted, as well as any attached atoms. Thus, you only need to click on the carbon to delete an entire methyl group. It is important to do an H/AD command before writing a file if any atoms or bonds were deleted. This ensures that any "holes" created but not removed from the arrays will be removed during this process and that the heavy atoms will be in the proper sequence. 5.10 Move This command moves an atom into a new position. After selecting MOVE click on the atom to be moved, then click in the new position. The structure is redrawn the atom will be moved. Multiple MOVEs may be done at one time, until another option is chosen. 5.11 Rotate Bond This command rotates the central bond of the four selected atoms. Use SELATM to first select the four atoms. The selected atoms will be marked by small gray dots. 5.12 Query This command is used to measure atom positions and charges. POAV, bond lengths, angles and dihedrals. To determine the position and charge of an atom, or obtain the POAV, select QUERY click on an atom and then a blank space on the screen. To measure a distance, select QUERY, click on the two atoms whose distance is to be measured, then click on a blank area of the screen. The distance between the two atoms will be displayed on the screen at the location of the last click. To measure an angle, click on the three atoms forming the angle of interest, then a blank area of the screen. The numerical value of the angle will be displayed. Similarly, to measure a torsion angle click on the 4 atoms of the torsion then a blank area. If you select two vicinal hydrogens or if you select four atoms of a dihedral and the first and last atoms are hydrogens the PMR coupling constant will be calculated. The PMR coupling constants are corrected for electronegativity according to the method of Haasnoot, DeLeeuw and Altona, Tetrahedron 1980, 36, 2783. Any number and combination of distances, angles and torsion angles may be measured, until another option is chosen. The queries can be printed and will remain on the screen during minimization and dynamics calculations so that changes in the structure can be monitored. To clear the values from the screen, click on UPDATE twice. 40 5.13 PT This command calls up a window containing a list of atom types. An atom may be changed to a different type by selecting the new type from the Periodic Table window, then clicking on the atom to be changed. Multiple atoms may be changed to the same type without re-selecting the type. A complete listing of atom types is given in the MMX Force Field chapter. Clicking on CANCEL closes this window. 5.14 Metals This command calls up a window containing a list of metal atom types. An atom may be changed to a particular metal by selecting the appropriate metal from the list, then clicking on the atom to be changed. The electron count (saturated, unsaturated, high spin, low spin or square planar), charge and coordination of a metal to a pi system are set with the Metal Coord menu item in the Mark Menu. Clicking on CANCEL closes this window. 41 5.15 Rings This command calls up a window containing a list of ring templates. A complete listing of the rings is given in Appendix B. Selecting a ring from the list causes that structure to be placed in the structure window as a new substructure. Clicking on CANCEL closes this window. 5.16 AA This command opens a dialog box containing 24 standard amino acid residues. Selecting one of the amino acids causes that structure to be drawn in the structure window. If the CONNECT box is selected, the secondary structure of the connection (alpha helix, beta sheet, beta turn type I or beta turn type II) must be specified prior to selecting the amino acid sequence. Clicking on CANCEL dismisses this window. A complete list of all the amino acids is given in Appendix B. 5.17 Su 42 This command opens a dialog box containing 25 standard sugar residues. Selecting one of the names causes the corresponding structure to be drawn in the structure window. If the CONNECT box is checked, the structure of the connection (alpha or beta) must be specified prior to selecting the sequence. Clicking on CANCEL dismisses this window. A complete listing of all the sugars is given in Appendix B. 5.18 Nu This command opens a dialog box containing 5 nucleosides. Selecting one of the names causes the corresponding structure to be drawn in the structure window. The default is to draw DNA, but clicking on the RNA button instead may draw RNA. If the CONNECT box is checked then a letter symbol representing the Nucleoside chosen will be written in the edit box. When all the nucleosides are entered selecting Build will generate a single strand of DNA or RNA. Selecting Build Double will build a double strand. Clicking on CANCEL dismisses this window. A complete listing of all the nucleosides is given in Appendix B. 5.18 Organo Metallics Templates This command calls up a window containing a list of organometallic templates. These are structures that have been built and saved in a file. Selecting a structure from the list causes that structure to be placed in the structure window as a new substructure, which can then serve as the starting point for building new structures. Clicking on CANCEL closes this window. 43 5.20 Transition State Templates This command calls up a window containing a list of transition state structures. These are structures that have been built and saved in a file. Selecting a structure from the list causes that structure to be placed in the structure window as a new substructure, which can then serve as the starting point for building new structures Clicking on CANCEL closes this window. 44 45 Chapter 6. Conformational Searching GLOBAL-MMX (GMMX) is a steric energy minimization program which uses the currently selected force field to search for the global energy minimum and other low energy local minima. Processing by GMMX is done in two stages. The first stages randomly searches over the selected rings and rotatable bonds and keeps all conformers within 3.5 Kcal of the lowest energy conformer found (Eminim) during the minimization. The second cycle reminimizes the structures found in the first cycle and keeps only those which are within 3.0 Kcal of the lowest energy conformer. The default energy windows for the two cycles can be changed. In addition to an output file containing the coordinates of the final structures, a textual summary file called '.pkm' is produced which lists the energy and Boltzmann distribution of each low energy conformation. This file may also include a listing of query operations (PMR coupling constants, distances, angles, and dihedrals) for each structure as well as a Boltzmann averaged summary. Although the conformational searching techniques that follow are unique in their approach, the methods described by the Still group (see M. Saunders, K.N. Houk, Y-D Wu, W.C. Still, M. Lipton, G. Chang, and W. Guida J. Am. Chem. Soc. 112, 1419 (1990) and references to previous work cited there in.) were the inspirational source for this work. The search techniques in GMMX are based on the methods used in BAKMDL, developed by Professor Kosta Steliou of Boston University, and ported to the MMX force field by Mark Midland of UC Riverside and Joe Gajewski and Kevin Gilbert of Indiana University. We wish to thank Professors Still and Steliou for sharing with us unpublished work and code that greatly enhanced our routines. Conformational space can be searched by GMMX in three ways. These are the Mixed method, the Bonds method and the Cartesian method. The Bonds method randomly selects a subset of the bonds designated by the user for rotation. Bond rotation can cause large changes in the shape of a molecule. The Cartesian method randomly moves a subset of all heavy and nonvolatile atoms in 3d space causing small changes in the shape of the molecule. The Mixed method alternates between the Bonds and Cartesian methods and is the preferred method. This procedure is especially efficient with 46 cyclic structures having side chains. You may select ring bonds for rotation as well as the side chain bonds but restricting the bond selection to the side chain bonds usually is all that is necessary if only 3 to 7 member rings are present. The coordinate (Cartesians) movements will apply to the entire structure. When GMMX is first selected from the Analyze Menu a dialog box will be presented as shown above. This dialog box controls the setup and running of GMMX. Items that can be set directly in this dialog include the jobname, the search method (bonds, coordinates or both (default)), and the energy windows for the first and second cycles. The buttons Setup Rings, Setup Bonds, Comparison Method, Setup Queries, Options, and Read Job all call up further dialog boxes to setup the various options. Save Job allows the user to save a file of the current GMMX options, and Read Job reads this file. Run GMMX starts the first cycle processing while Run 2nd Cycle starts the job in the second cycle, which presumes that a file of structures saved from the first cycle is available. 6.1 Setup Rings GMMX will automatically search for all rings in the current structure and the results will be listed in a scrolling list window. To search on a particular ring select that ring from the list of rings and the select the Add button. In molecules containing fused or multicyclic ring systems all possible permutations of the rings will be listed. Thus trans decalin will have entries for two six membered rings and one ten membered ring. Care should be taken in selecting the correct ring entry to search. During the search the ring will be broken between the first two atoms of the Atom Number list. These are displayed as Closure Atom 1 and 2. The Closure Atoms may be edited but they must be adjacent atoms. 47 6.2 Setup Bonds To designate rotatable bonds select the Setup Bonds option in the dialog box. A new dialog box will be shown. The atom numbers of the rotatable bond can be entered in the edit boxes. When the ADD button is selected the atom numbers are read and checked to see that a bond exists between the two atoms. If a bond is found then the default rotation increment for this bond is then determined and the bond is added to the scrolling list of bonds for searching. Bonds may also be entered by using SelBnd from the Draw Tools. To use this option, select the bonds before bringing up the Setup Bonds dialog box. The selection may be done while the main GMMX dialog box is up. Just move the box to the side and rotate and select the bonds. When Setup Bonds is selected, the selected bonds will appear in the scroll list. To delete a bond, select the bond from the scrolling list and then select Delete. Bond Resolution If the bond is an ester or an amide, the resolution set will have two angles (0 and 180 degrees). If the bond is an SP3-SP3 bond, then three angles are used (0, 120, and 240 degrees). If the bond is SP3-SP2, twelve angles are considered (0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, and 330). If the bond is SP2-SP2, 6 angles are chosen (0, 60, 120, 180, 240, and 300). Finally, if the bond is a ring bond, then if the ring is 10 atoms or less, the resolution set will have 12 angles of 30-degree increments as above and if it is 11 atoms or more, 6 angles of 60-degree increments will be used. The user can override these default settings (except for no-rotatable bonds) and enter their own values. Additional Ring Information For each ring defined, GMMX will calculate closure angles and a closure window. Again, the user can accept these values or enter others. Within GMMX each bond is randomly rotated by each angle in the resolution set. The newly created geometry is then analyzed to see if each ring can be reclosed within the defined limits of closure. It is checked for bad 1,5 C-C VDW interactions and trans annular interactions. Structures with up to 2 additional bad 1,5 CC VDW interactions beyond the original structure may be kept. The structure is also screened for epimerizations and all other constraint criteria such as distances, dihedral angles etc. imposed during the interactive procedure. If all the constraint criteria are satisfied, the conformer is processed by GMMX. 6.3 Setup Query The Setup Queries dialog box allows one to specify query information for the second cycle. Clicking on the four options will bring up dialog 48 boxes for entering atom numbers. For distances the atom numbers must be entered in sets of 2, for angles sets of 3, for dihedrals sets of 4 and for coupling constants sets of 2. This process may be automated by performing the query on the structure on the screen. This may be done prior to setting up GMMX or while the main GMMX dialog box is on the screen. Use Query on the Draw Tools. When one of the four options is selected, the query information will appear in a scroll list. The final output file, jobname2.pkm, will contain a list of the queries for each structure as well as a summary total based on a Boltzmann average. 6.4 Comparison Method The Comparison Method dialog box allows one to choose various options for structural comparisons during the search. The default is to compare all nonvolatile atoms. Nonvolatile atoms are those that are not removed in an H/AD operation, i.e. all heavy atoms and hydrogens on O or N. The equivalent atoms and Specific Sequence options have not yet been implemented. Numerical isomers are found in unsubstituted rings such as cyclooctane. Reflection isomers are found in unsubstituted acyclic compounds such as butane. A set of specific atoms may be compared by clicking the Specific non-volatile atoms box and entering a set of numbers in the edit box. The default comparison routine uses a fast analytical method during the first cycle and a slower but more accurate method during the second run. It is usually better to err on the side of over collecting on the first run and then weed out duplicates on the second run. 49 6.5 Options The Options dialog box allows one to change several options for the search. Chirality will be checked and enantiomers rejected if the box is checked. Hydrogen bonding will be on by default. If the system has pi atoms turned on, a pi calculation will be performed. Note that this may not be necessary and may require more time for rigid systems like benzene. By default, structures will be screened for bad 1,5 interactions and rejected if found prior to minimization. Conformational enantiomers such as the two gauche forms of butane will be kept. An early bail out of the minimization can be done. This applies a sliding high energy cut off of 5-15 kcal/mol above the minimum energy found to the structure during the 50-100 iterations of the first-derivative minimization. If the structure is 15+ kcal/mol above the lowest energy structure at the 50th iteration, it will be rejected and the search will move on. This cut off is not used during the second cycle. This method may lead to premature bail out if there are a lot of hydrogen bonds in the structure. The structures will be sorted by energy. The option to sort by heat of formation has not been implemented. The Boltzmann temperature is used to calculate the distribution of isomers. The cutoff distance and energy are used during structure comparisons. During both cycles all structures within 0.25 kcal/mol of the current structure will be examined. During the first cycle a structure will be considered to be unique if any atom is more than 0.25 Angstroms away for the least squares fit. In the second cycle the RMS average must be greater than 0.25 Angstroms. The random number generator uses the seed value. A search starting with the same starting structure will always follow the same path unless the seed value is changed. The search will stop after the lowest energy structure (emin) has been found 5 times or there are 25 duplicates in a row without a new structure. However at least 50 structures must be minimized. The default number of duplicates required is 2.5 times the number of heavy atoms with a maximum of 50. The search will also stop if 100,000 structures have been minimized. 6.6 Run GMMX Once all the setup is done GMMX can be run. In all methods the original structure is minimized to generate the initial minimum energy conformation. The structure is then modified by either the bonds or Cartesian method and the new conformation is checked for bad-1, 5 50 interaction, and epimerization. If all the acceptance criteria are satisfied, the structure is minimized. If the minimization yields an energy acceptable conformer that HAS NOT BEEN FOUND BEFORE, it is saved and its geometry is used to spawn a new conformer, otherwise, it is rejected. Only accepted conformers are permitted to carry-on the search. If attempts to create a new conformer fail, based on the acceptance criteria, it is sent back to try again until a NEW ACCEPTABLE conformer is created. Statistical searching on coordinates should be selected whenever a rigid or fused polycyclic system is to be analyzed. If there are side chains then the Mixed procedure should be favored. The Bonds method is best for acyclic structures. 6.7 Run 2nd Cycle Run GMMX will automatically run the first and second cycle of the search. The second cycle refines the structures found in the first cycle by throwing out unnecessary duplicates and cutting down the energy window. It also performs any Query operations. The structure output files from both searches are kept. You can send the search output through the second cycle at a later time by using this option. The run will use any criteria (such as Query information) which you have selected. 6.8 Save Job This option will bring up a file-save dialog box. The default file name will be the Job Name entered in the GMMX dialog box. The file save will save .pcm and .inp files. The inp file contains the name of the pcm structure file and the directions for doing the search. Thus the pcm file cannot be deleted or renamed if you wish to run this job later. The inp file may be read by the DOS or text-based version of GMMX. 6.9 Read Job This option brings up a file read dialog box and reads the inp file saved in Save Job. All options will be updated to the settings in the job file 51 52 Chapter 7. File Menu This menu contains the following commands: Open Save Save Graphic Save Movie Print Read pcmod.bak Exit Reads a file containing a molecular system Writes a molecular system to a file Writes a file containing a picture of the screen Writes a file containing a Movie Print the current molecular system Read the structure backup file Exit PCMODEL 7.1 Open The OPEN option in the FILE menu is used to read a new structure file into PCMODEL. Any structure on the screen will be erased. Macintosh: Selecting OPEN immediately brings up a standard Macintosh file open dialog box with the different file formats listed in a drop down window at the bottom of the dialog box. Windows and Linux: Selecting OPEN immediately brings up a standard Windows Open File dialog box which gives the current path, an edit window for the filename, a drop down box containing the various file types supported by PCMODEL, a window 53 listing directories and disk drives, and a scrollable window listing the files in the current path (if a wildcard expression is used for the filename). When the dialog box first appears, the PCMODEL file type is selected and all files with the .pcm file extension will be shown. A filename may be entered by typing the name in the filename edit box or by selecting (with the mouse) a file from the scrollable file list box. To see files available in the current path, use a wildcard expression such as *.PCM to see all files with the PCM extension, or *.* to see all files. PCMODEL supports several different types of files. Clicking on the combo box at the bottom of the dialog box will show all the types of files that can be read in PCMODEL. The default file type is PCMODEL. File Types Read by PCMODEL PCMODEL files contain information about all the atoms and bonds in a molecule, including information about hydrogen bonding, pi atoms, metal coordination and substructure membership. It is the most general file type for molecular mechanics information, is a free format ASCII text file, and can be read or edited with any word processor. A PCMODEL file can contain either one structure or multiple structures. PCMODEL files can be read by Gaussian 92 and can serve as input to this ab initio quantum chemistry program. (A full description of this file type is given in chapter 16.) MMX files are essentially MMP2 formatted files (see QCPE program number 395 for a detailed description). These files contain information about atoms and bonds in a molecule, including information about pi atoms, hydrogen bonding and metal coordination, but not substructure membership. An MMX file can contain either one substructure or multiple substructures. It is an ASCII text file with a fixed, Fortran format, and can be read or edited with any word processor. The fact that it is fixed format means that data must be entered in specific columns to be read correctly, which makes editing difficult. (A full description of this file type is given in chapter 16.) MM3 files contain information about all the atoms and bonds in a molecule written in the MM3 format and using MM3 atom type rules. MM3 files are text files and use a Fortran type fixed format. The files may be edited with a text processor, but the fixed format requires that data be entered in specific columns to be read correctly. PDB files are structure files using the Protein Data Bank format developed at Brookhaven National Laboratory. The PDB format can be used to describe any molecule and is not restricted to proteins or nucleic acids. The PDB format contains information about the atom type, the residue name if part of a protein or nucleic acid, and the atomic coordinates of the atom. Bonding information may be included in the file but it is not required. PCMODEL reads PDB files and tries to determine the bonding arrangement based on internuclear distances. While this method is good it is not perfect and the bonds shown when a PDB file is read should be looked at carefully before further calculations are attempted. 54 MOPAC INP and ARChive files are used by the semi-empirical quantum chemistry programs, AMPAC and MOPAC (QCPE program number 514). These files contain a list of atom symbols, bond lengths, angles and dihedral angles, but no information about bonding. MOPAC files may be used for input to the AMPAC, MOPAC and Gaussian programs since all of these programs can read and interpret internal coordinates. The INP file is an input file to AMPAC or MOPAC in Z matrix format and the ARChive file is the archive output file written by Mopac (normally FOR012) and contains the optimized geometry in Z matrix form and the atomic charges calculated by Mopac. Both the structure and charges can be read into PCMODEL. Alchemy and Sybyl molecular modeling programs marketed by Tripos Associates (St. Louis, MO) use ALCHEMY and SYBYL files. Alchemy file format is also used by Chemical Abstracts Service for 3D-structure information. MACROMODEL files are molecular mechanics type files generated by the Macromodel program. This large molecule modeling program, developed by C. Still, Columbia University, runs on workstations and provides many facilities for handling large molecules. Macromodel files contain information about atoms and bonds, but no information about pi atoms, hydrogen bonding or transition metals. X-RAY files are free format structure files in a format that has been developed for reading x-ray crystal data. X-ray structure files only contain information about atom types and positions. (A full description of this file type is given in chapter 16.) CHEM-3D is a molecular modeling program developed by Cambridge Scientific Software for use on a Macintosh computer. PCMODEL reads and writes the Cartesian type II structures. Chem-3D can be used to generate publication ball and stick pictures. TINKER is a molecular modeling program developed by Professor Jay Ponder of Washington University ([email protected]). PCMODEL reads and writes the xyz cartesian filetype. MDL_MOL files are structure information files in the molfile format developed by MDL Information Systems Inc. Molfiles can be generated by programs such as Isis™ Draw, or as the result of a search of the REACCS or MACCS databases. Molfiles contain 3-D structure and bonding information. SDF are structure files generated by the structure building programs Corina and Concord and can also be output by Isis Draw (as 2D files). Gaussian files are the output files (text) written by the Gaussian Quantum Chemistry programs running under Windows, on a workstation or supercomputer. Since PCMODEL reads the text file, the output file is portable across all these platforms. 55 Gaussian ChkPt files are the formatted checkpoint files generated by the Formchk utility of the Gaussian program. Jaguar Input and Log files are input and output files written by the Jaguar quantum chemistry program from Schrodinger, Inc. CSSTR files are Cambridge Structural Database files. Gamess files are the output files (text) written by the Gamess Quantum Chemistry programs running under Windows, Macintosh, on a workstation or supercomputer. Since PCMODEL reads the text file, the output file is portable across all these platforms. Hondo files are the output files (text) written by the Hondo Quantum Chemistry program. Since PCMODEL reads the text file, the output file is portable across all platforms. ADF files are the output files (text) written by the Amsterdam Density Functional quantum chemistry program. Since PCMODEL reads the text file, the output file is portable across all platforms. Turbomole files are the output files (text) written by the Turbomole quantum chemistry program. Since PCMODEL reads the text file, the output file is portable across all platforms. PQS files are the output files (text) written by the Parallel Quantum Systems (PQS) quantum chemistry program. Since PCMODEL reads the text file, the output file is portable across all platforms. Smiles strings are a linear, 1D, notation for chemical structures. Pcmodel reads the string and attempts to build a 3D structure based solely on the atom types and connectivity. 7.2 Save The SAVE option is used to write the current molecular system to a disk file. Macintosh: Selecting Save brings up a dialog box listing the current types of files PCMODEL can write. Select the appropriate file format and then OK. The standard Macintosh file save dialog box will then be presented. Windows and Linux: Selecting SAVE brings up a standard Windows File Save dialog box which gives the current path, an edit window for the filename, a list box containing the various file types supported by PCMODEL, a window listing directories and disk drives, and a scrollable window listing the files in the current path (if a wildcard expression is used for the filename). All files with the default extension will be shown. 56 The last file name used will be retained. If this file is used again, you will be asked if you want to replace the file or append the structure onto the existing file. When the dialog box first appears, a wildcard expression is displayed in the filename edit box, and the PCMODEL file type is selected. All files that match the wildcard expression will be listed in the file list box. A filename may be entered by typing the name in the filename edit box or by selecting (with the mouse) a file from the scrollable file list box. To see files available in the current path, use a wildcard expression such as *.PCM to see all files with the PCM extension, or *.* to see all files. If the filename that is entered already exists, a dialog box will appear asking if the new structure is to be appended to the existing file, or if the existing file is to be replaced. Choosing APPEND to generate multiple structure files or libraries of related structures. The current directory is given in the current path box. The directory list box displays all directories below the current directory, the directory one level up from the current directory ([..]), and all other disk drives on the computer. The current path may be changed by selecting either another directory or disk drive in the directory list box. PCMODEL supports several different types of files. Clicking on the combo box at the bottom of the dialog box leads to a drop down menu of all the files written by PCMODEL. The default file type is PCMODEL. MMX atom types are assumed for all files except MM3 files where the MM3 atom types are assumed. File Types Written by PCMODEL PCMODEL files contain information about all the atoms and bonds in a molecule, including information about hydrogen bonding, pi atoms, metal coordination and substructure membership. It is the most general file type for molecular mechanics information, is a free format ASCII text file, and can be read or edited with any word 57 processor. A PCMODEL file can contain either one structure or multiple structures. PCMODEL files can be read by Gaussian 92 and can serve as input to this ab initio quantum chemistry program. (A full description of this file type is given in chapter 16.) MMX files are essentially MMP2 formatted files (see QCPE program number 395 for a detailed description). These files contain information about atoms and bonds in a molecule, including information about pi atoms, hydrogen bonding and metal coordination, but not substructure membership. An MMX file can contain either one substructure or multiple substructures. It is an ASCII text file with a fixed, Fortran format, and can be read or edited with any word processor. The fact that it is fixed format means that data must be entered in specific columns to be read correctly, which makes editing difficult. (A full description of this file type is given in chapter 16.) MM3 files contain information about all the atoms and bonds in the molecule. The MM3 atom types are used and pi atom marking is supported. MOPAC and AMPAC files are used by the semi-empirical quantum chemistry programs, AMPAC and MOPAC (QCPE program number 514). These files contain a list of atom symbols, bond lengths, angles and dihedral angles, but no information about bonding. MOPAC files may be used for input to the AMPAC, MOPAC and Gaussian programs. The dialog box will facilitate writing the file. 58 ALCHEMY and SYBYL files are used by the Alchemy and Sybyl molecular modeling programs, marketed by Tripos Associates (St. Louis, MO). Alchemy format is also used by Chemical Abstracts Service for 3D structure information. MACROMODEL files are molecular mechanics type files generated by the Macromodel program. This large molecule modeling program, developed by C. Still, Columbia University, runs on workstations and provides many facilities for handling large molecules. Macromodel files contain information about atoms and bonds, but no information about pi atoms, hydrogen bonding or transition metals. CHEM-3D is a molecular modeling program developed by Cambridge Scientific Software for use on a Macintosh computer. Chem-3D can be used to generate publication ball and stick pictures. Tinker is a molecular modeling program developed by Professor Jay Ponder of Washington University in St Louis. PCMODEL generates an xyz cartesian file that can be read by Tinker. PDB files contain the Cartesian coordinates of the current structure written in PDB format. Jaguar Input files are written for the Jaguar quantum chemistry program. They include the Cartesian coordinates of the structure and the atomic symbol. Gaussian Job files are input files for the Gaussian quantum chemistry program. Structural information can be output in either Cartesian or Z matrix format and many options may be set using the dialog box. The Keywords section is updated each time an option is selected. If you wish to add additional keywords not available through the options, they should be added just before OK is selected. Gamess input files will bring up a dialog box similar to the Gaussian box. Hondo input files will bring up a dialog box similar to the Gaussian box. SDF are structure files generated by the structure building programs Corina and Concord. ADF files are the input files (text) for the Amsterdam Density Functional quantum chemistry program Since PCMODEL writes a text file, the file is portable across all platforms. Turbomole files are the input files (text) for the Turbomole quantum chemistry program. Since PCMODEL writes a text file, the file is portable across all platforms. 59 PQS files are the input files (text) for the Parallel Quantum Systems (PQS) quantum chemistry program. Since PCMODEL writes a text file, the file is portable across all platforms. Smiles strings are a linear, 1D, notation for chemical structures. 7.3 Save Graphic This option saves the screen in one of the following file formats; GIF, BMP, HPGL, PostScript or POVRAY. The file may then be imported into other programs for editing. The POVRAY option will write a file for input into the rendering program POVRAY. This program is freely available for a number of platforms (PC, Mac, UNIX) at http://www.povray.org. It will provide a ray-traced picture of the molecule as shown to the left for potassium 18-crown-6. 7.4 Save Movie Save Movie writes a file in AVI format. The current options are to Rotate the structure about X, about Y, about Z, about X then Y and Rotate Bond. Any view of the molecule can be used. This is a method for generating short movie excerpts for lectures or PowerPoint presentations. 7.5 Print Print sends the current structure and related information to the default Windows printer (which may be a file). The Print Manager handles printer selection in WindowsTM or by the Chooser on the Macintosh. When PRINT is selected, a dialog box appears containing the currently selected printer. If the current structure is drawn as a stick figure then a dialog box will be shown with options for printing the current structure and 60 compare or energy windows. If the current structure is drawn in Ball and Stick, Tubes or CPK modes then the second dialog box will not be shown and the output and compare windows will not be printed. Any information in the structure window (such are queries) will be sent to the printer along with the structure. 7.6 Read pcmod.bak Every time a minimization is started and upon its completion a structure file, pcmod.bak, is written to the current working directory. This option will read in this file. 7.7 Exit This option leaves PCMODEL and returns to the operating system. A dialog box asks for confirmation before exiting. Note that any unsaved work will be lost when PCMODEL is exited. 61 62 Chapter 8 Edit Menu The EDIT menu contains the following commands: Draw Erase Structure Name Hide Hydrogens Epimer Enantiomer Remove LP Retype Set Atom Type List Atom Types Read Pcmod.Out Read Pcmod.Err Copy__To_Clipboard Orient_XY Plane Orient_XZ Plane Orient_YZ Plane Build Solvent Box/Solvate Build Periodic Box Recovers the TOOLS menu Erases all structures Edit or enter name of current structure This option toggles display of hydrogen atoms on and off. The hydrogens are not removed from the structure, merely un-displayed. This allows for a much clearer drawing without changing the geometry as with H/AD. Epimerizes the selected atom by interchanging the two selected attachments. Reflects the structure through a specified axis. Remove lone pairs from heteroatoms. Force PCMODEL to retype the current structure. Sets the atom type of the selected atom Lists all the atom types in the current force field Read Pcmod.out into a simple text editor. Read Pcmod.Err into a simple text editor. Copies an image of the structure window to the clipboard. Orient the molecule in a specified plane, placing the first selected atom at the origin, the second atom along the axis and the third atom in the plane. Useful when generating structures for MO calculations Build a box of solvent molecules or solvate the current structure. Build a periodic box from the current structure. 8.1 Draw The DRAW option brings back the Drawing Tools buttons if they are not visible, or makes them the active window if they are visible. Otherwise, this command does nothing. The commands in this Tool bar are described in detail in chapter 5 of this manual. 63 8.2 Erase This command erases the current structure and resets the default conditions for modeling. Since any unsaved structures will be lost, a dialog box appears and confirmation is required before the structure is actually erased. 8.3 Structure name This option brings up a dialog box for entering or editing the name of the current structure. The default structure name is "untitled". If a file containing a named structure is read, then the current structure name is replaced by the name from the file. The structure name is displayed in the title bar of the PCMODEL window, just to the right of the word "PCMODEL". The structure name is limited to 60 characters and will be written into the structure file whenever the structure is written to disk (if the filetype selected supports structure names). 8.4 Hide Hydrogens This option toggles the display of hydrogens attached to carbon. The atoms are still present in the structure database they are just not displayed. This will often make the display less cluttered, especially if atom numbers or types are being displayed. 8.5 Epimer This option allows for inversion of the stereochemistry at a particular chiral center. Before selecting EPIMER, the central atom and the two attachments to be switched must have been selected with the SELECT command from the TOOLS menu. Once the three involved atoms have been SELECTed, the EPIMER option can be chosen and the position of the two attachments (and all atoms attached to them) will be exchanged. This option will not work if the two attachments are connected to each other in a chain. 8.6 Enatiomer This option allows for enatiomerization of the structure by reflecting through an axis selected by the user. 8.7 Remove LP This option forces immediate removal of lone pairs from heteroatoms. Only the MMX force field uses lone pairs and lone pairs are normally removed automatically when calculations are done with any other force field. However, you may force removal of lone pairs with this option. 8.8 Retype This option forces PCMODEL to retype the current structure. 64 8.9 Set Atom Type This option allows the user to specify the atom type of the currently selected atom. This option is often used in conjunction with added parameter files to define new atom types or to redefine old atom types that are not recognized by the atom type parser. The selected atom will not be retyped automatically. 8.10 List Atom Types List all the atom types in the currently selected force field. 8.11 Read Pcmod.out This option forces PCMODEL to close the output file, Pcmod.out, and read the file into a text editor. This allows the user to view the output of a calculation without exiting Pcmodel. If there is an error with missing constants that information will be written into Pcmod.out. Once the editor is started it can be used to read the appropriate parameter file to add the missing constants. . 8.12 Read Pcmod.err This option forces PCMODEL to close the error file, Pcmod.err, and read the file into a text editor. If there is an error with missing constants that information will be written into Pcmod.err and the calculation will stop. The only information in the error file is the type of constant missing and the atom types. Once the editor is started it can be used to read the appropriate parameter file to add the missing constants. 8.13 Copy_To_Clipboard Selecting this option copies the current structure window to the clipboard with all color information intact. The clipboard can then be copied into a paint program for editing, or it can be printed when a color printer is available. 8.14 Orient_XY Plane Orient_XZ Plane Orient_YZ Plane These commands will orient the molecule in the selected plane. Select three atoms using the Select command from the DrawTools menu, then select one of these options. The first selected atom will be placed at the origin, the second atom will be placed along the axis and the third atom will be rotated to lie in the plane specified. This option is useful for orienting a structure before writing an input file for a molecular orbital calculation. 8.15 Build Solvent Box/Solvate 65 This option is used to build a box of solvent molecules or to solvate the current molecule. If there is molecule in the structure window when this dialog is called the dimensions of the smallest box enclosing the current structure will be calculated and displayed in the Mol Dimensions edit boxes. The default solvent is set to water but may be changed to chloroform, octane or to the current structure. The number of molecules desired must be entered and the density may be changed at this time. The cell size that is required to contain the current structure and the number of solvent molecules at the entered density is computed and displayed in the Cell Size edit boxes. Hitting the OK button will causes the solvent molecules to be added and the dialog box dismissed. If there is a current structure on the screen it will be moved to the center of the box and the remainder of the molecules will be added using the skew start method of Refson (K. Refson, Moldy v 2.9 …..). The skew start method works well for small, compact molecules whose dimensions are nearly spherical. If you want to build boxes of odd shaped molecules, those whose dimensions are elongated in one dimension, then you should use the Build Periodic Box command discussed below. Upon exiting this dialog the force field calculations are set to use Periodic Boundary Conditions for minimizations and dynamics calculations. We currently use a minimimum image convention, a spherical cutoff for dispersion interactions and a particle mesh ewald method for long range electrostatic interactions. Due to the organization of the code in PCMODEL these calculations are currently very slow and PCMODEL is probably not the program of choice for production dynamics calculations. However for short runs, initial testing and visualization PCMODEL works fine. 8.16 Build Periodic Box 66 This menu options is useful for building periodic boxes of oddly shaped molecules. There must be a molecule currently on the screen for this dialog to function. The molecular dimensions of the current structure are computed and displayed in the Mol Dimensions edit boxes. The number of molecules to include in the box and the desired density must be input. Calc Cell Size computes the cubic cell required to hold the number of molecules at the current density. Build Cell adds the appropriate number of molecules to the cell using the “skew start” method (see above). The resulting cell can then be visually examined for bad non-bonded interactions and a single point energy calculation done to assess the extent of bad non-bonded interactions. If there are severe molecular overlaps the added molecules can be erased using the Reset Cell button which returns the cell to its initial state. The density can then be changed and the process of building the cell can be repeated. By this interactive method a reasonable starting cell can be obtained without severe non-bonded interactions. Energy minimization followed by dynamics runs with increasing densities can be used to build a relaxed cell at the density desired for study. 67 68 Chapter 9 View Menu This menu contains the following commands: Control Panel Labels Mono/Stereo Stick Figure Ball and Stick Pluto Tubular Bonds CPK Surface Dot Surface Ribbon RedGreen Stereo Top View Dipole Moment Brings up a dialog box to scale, translate and rotate structures in the structure window. Brings up a dialog box to change the structure labels Toggles between mono and stereo display Display all structures as stick figures. Display all structures as Shaded ball and stick figures. Display all structures as Pluto type ball and stick figures. Display all structures with tubular bonds. Display all or selected structures with CPK surface. Display all or selected structures with dot surface. Display a Ribbon diagram of peptide or nucleic acid backbone Toggles red/green stereo display. Turns on/off a top view of the current structure Draws a dipole moment along with structure. 9.1 Control Panel Selecting CONTROL_PANEL brings up a dialog box containing seven controls which allow scaling, translation and rotation of the current molecular system. The SCALE control allows the structure to be reduced or enlarged. Enlarging the structure is useful when trying to select atoms in congested systems, and reducing the structure can be useful when visualizing large structures. The three TRANSLATE controls move the molecular system in the X, Y, or Z directions. The X direction is horizontal on the screen, the Y direction is vertical, and the Z direction is perpendicular to the screen. The three ROTATE controls rotate the system around the respective axes. RESET_VIEW returns the molecular system to the coordinates it had when the CONTROL_PANEL option was selected. All translations and rotations are reset, but changes in scale remain in effect. RESET_SCALE resets the scale size to the default value. It has no effect on rotations or translations. 69 EXIT dismisses the dialog box. To move one substructure relative to other substructures, use the MOVE command under the SUBSTR menu. 9.2 Labels Selecting LABELS brings up a dialog box through which the currently displayed labels can be changed. The default is to only show bonds. Clicking on "OK" will close this window, with the selected display type enabled, and this display type will be remembered and made the default when you exit PCMODEL.. The options are: Hydrogrens and lone pairs - places the letter "H" at each hydrogen position, and displays lone pairs as a pair of dots. This does not add hydrogens or lone pairs, it only displays them if they exist. Bonds only (default) - removes all atom symbols from the display, but atoms and bonds are shown in their normal colors. This is especially useful with large structures which quickly become cluttered when atom symbols are displayed. Atom numbers - labels each atom with its individual atom number. This is useful for setting up files for GMMX, the global searching program, which works on atom numbers. It is also useful when trying to interpret output given in terms of atom numbers. MMX Atom Types - labels each atom with its MMX atom type number. This is useful for examining parameters used in the MMX calculations, since these are given by atom type. (see Chapter 7 for a complete list of atom types and the corresponding numbers). MM3 Atom Types - labels each atom with its MM3 atom type number. This is useful for examining parameters used in the MM3 calculations, since these are given by atom type in the file MM3.PRM. MMFF94 Atom Types - labels each atom with its MMFF94 atom type number. This is useful for examining parameters used in the MMFF94 calculations, since these are given by atom type in the file MMFF94.PRM. AMBER Atom Types - labels each atom with its Amber atom type number. This is useful for examining parameters used in the Amber calculations, since these are given by atom type in the file AMBER.PRM. Oplsaa Atom Types - labels each atom with its Oplsaa atom type number. This is useful for examining parameters used in the Oplsaa calculations, since these are given by atom type in the file OPLSAA.PRM. Atomic Charge - labels each atom with its current atomic charge. This will be zero (0.0) until a calculation is done, and the charges will be specific to the force field used in the calculation. 70 Substructure number - labels each atom with a number representing its substructure membership. This number is a value form 0 to 255 and is the sum of 2substructure number for all substructures for which the atom is a member. Color by substructure - colors the bonds by the lowest substructure number at each atom. Color by Strain - During a calculation the energy for each interaction is partitioned by atom. The individual atomic energy components are then normalized and colors are assigned to each atom based on the magnitude of the energy with Red being the most energetic, followed by rose, yellow, green, cyan, magenta, blue and gray. 9.3 Mono/Stereo This option changes the default display between one structure (Mono) and two structures displayed side by side in stereo. The stereo display can be rotated inward or outward, though the use of STEREO option in the OPTIONS menu. In stereo mode the two structures are rotated + and - three degrees from the mono structure to simulate a stereographic display. 9.4 Stick Figure Selecting this option returns the current drawing mode to the default stick figure display of all atoms. 9.5 Ball and Stick Selecting this option displays the current structure with small balls representing the atoms and tubular bonds connecting the atoms. 9.6 Pluto Selecting this option displays the current structure as a Pluto type ball and stick figure with shading. 9.7 Tubes Selecting this option displays the current structure with thick bonds. 9.8 CPK_Surface This option displays the current molecular system as a CPK model 71 9.9 Dot_Surface This option displays the current molecular system with a dot surface around it. 9.10 Ribbon This option draws a ribbon for the backbone of a peptide or nucleic acid chain. The display can be of the ribbon only, or the ribbon and a stick representation of the structure itself. The type of molecule (acyclic protein, cyclic protein or DNA/RNA) must be indicated. The dialog box offers a choice of Oxygen-Oxygen (default) or swapped orientation of the ribbon. Oxygen-oxygen produces smooth ribbons for alpha helices, while swapped produces smooth ribbons for sheets. The algorithm searches for the first N-terminus and draws the ribbon from there. Once it cannot find another amide linkage in the chain, it stops there and draws the ribbon. The ribbon display remains in effect until either the STICK_FIGURE option is selected or the Ribbon dialog box is brought up and canceled. The ribbon display can be rotated and translated, and can be printed. 9.11 Red/Green Stereo Redraws the current structure in stick figure form using red and green images to create a stereo image when viewed through red/green glasses. 9.12 Top View Draws a second view of the current structure rotated by 90 degrees. The top view is smaller and placed in the upper or lower corner, but this allows two views of the same structure simultaneously. 9.13 Dipole Vector Draws a vector representing the computed dipole moment of the current structure. The dipole vector will be rotated with the current structure. 72 73 Chapter 10 Compute and Force Field Menus This menu contains the following options: Minimize Minimize the current structure(s). Single Point Calculate the energy of the current structure(s). User External Charges Use charges read from external file, usually Mopac/Ampac Use Gasteiger Charges Assign charges based on Gasteiger’s sigma method Normal Vibrational Modes Compute normal vibrational modes Mopac Run the semi-empirical quantum program Mopac Ampac Run the semi-empirical quantum program Ampac Gaussian Run the quantum chemistry program Gaussian Gamess Run the quantum chemistry program Gamess PQS Run the quantum chemistry program PQS (Linux version only) Orbitals View the molecular orbital or electron densities calculated in Mopac, Ampac, Gaussian, Jaguar, or Gamess Vibrations View the normal vibrational modes calculated in Mopac, Ampac, Gaussian, Jaguar, Gamess or PCMODEL GMMX Run the stochastic conformational search. Metropolis MC Run the Monte Carlo conformational search. Vibrational Mode Search Run search using low frequency vibrational modes Dynam Molecular Dynamics simulation. Auto Dock Simulated annealing search of lowest energy interaction between two structures. Manual Dock Move the current substructure about the main structure and compute the energy at each step Batch Read a multiple structure file and minimize all structures or compute properties. Rot_E Rigid rotor evaluation of rotational energy barrier. Dihedral Driver Grid search with minimization evaluation of the rotational energy barrier. Relaxed Grid Search Use Grid search as starting point then minimization without fixing the dihedral angle. Force Field Menu MMX MM3 MMFF94 AMBER Oplsaa Use the MMX force field. Use the MM3 force field Use the MMFF94 force field Use the Amber 95 force field. Use the Oplsaa force field. 74 10.1 Minimize This option optimizes the geometry of the current molecular system using the currently selected force field. The current molecular structure is analyzed for atom types, bonds, angles and dihedral angles and the appropriate constants are extracted from the database of parameters. These parameters are found in the text files mmxconst.prm, mm3.prm, mmff94.prm amber.prm or oplsaa.prm. The energy of the molecular system is evaluated and written to the screen in the Output window, and then the minimizer is called. The default action of the minimizer is to first do a first derivative minimization until the gradient falls below 1, then a second derivative minimization until the gradient falls below 0.0001. The minimizer attempts to lower the energy of the system by moving the atoms. Every 5 iterations during the first derivative minimization, and then ever 2 iterations during the second derivative minimization the Structure window is updated with the current geometry and the Output window is updated with the iteration number, the atomic movement (in 10-5 Å units) and the energy (in kcal/mol). If the energy goes up, or if the energy difference between two calculations falls within the convergence criterion the calculation is stopped, the final energy and its components, the heat of formation (for MMX and MM3 force fields) and the SE (strain energy) are written to the Output window, and the Structure window is updated. In general, the energy minimum found will be a local energy minimum. A calculation may be stopped at any time by clicking the Stop Job dialog box. The results, in abbreviated form, are written to the file pcmod.out. This file is a record of all the minimizations done during the current session and can get quite large. The default is to generate a minimum output, but this may be changed with the Printout command in the Options Menu. Pcmod.out is overwritten every time you start PCMODEL, so the file must be renamed to preserve a record of a particular set of calculations. A structure file, in PCM format, is automatically saved upon starting the minimization and after every five iterations so that if the program crashes or is stopped the last structure can be recovered. The filename is pcmod.bak and it is written in the current directory. This file is overwritten every time a new minimization is begun, so to preserve a structure it must explicitly saved with the Save command. The PCM file format is the most concise way to save data since the energy data can be regenerated by repeating the energy minization with the final optimized geometry. A major problem in minimizing structures drawn without a template is that hydrogens and lone pairs are often forced into inappropriate positions resulting in high energy structures. It is a good idea to do an H-delete-H-add sequence (select H-A/D in the TOOLS menu twice) then reminimize. For large structures, reminimize to be sure the structure is fully converged. Since minimization is quite time-consuming with large molecules, it is often economical to minimize the structure without added hydrogens to get the three-dimensional structure approximately right prior to H-A/D and final minimization. In the MMX force field PCMODEL has access to a number of generalized force field parameters ( i.e., torsional potentials dependent only on the two central atoms) to which the program defaults if no standard MMX parameters are available. These parameters are not optimal and energies produced with them should be considered 75 accordingly (however, geometries should not be too far off). The use of generalized parameters is always noted in the output file PCMOD.OUT. It is important to note that the MMX energy resulting from a minimization with a pi calculation does not contain the potential energy of the pi system. So a comparison of MMX energies for isomeric pi systems is invalid, just as a comparison of MMX energies is invalid for structural isomers. A comparison of the heats of formation, on the other hand, is appropriate. The only circumstance where MMX energies may be compared directly is with conformers or diastereomers. 10.2 Single Point SINGLE POINT does a single calculation of the energy of the current structure(s). The calculation is begun just as for the MINIMIZE option, however the calculation is stopped before the minimizer is called. The heat of formation is not calculated during a single point calculation. 10.3 Use External Charges This option forces PCMODEL to use any charges that were read into the program from an external file. This option is often used with Mopac or Ampac files where the charge is computed and included in the archive file. At this time charges are not read for Gaussian, Gamess, Hondo or Turbomol files. 10.4 Use Gasteiger Charges This option forces PCMODEL to use charges computed by Gasteiger’s sigma model (Gasteiger and Marsili, Tetrahedron, 36:3219-3288, 1980) . 10.5 Normal Vibrational Modes Since PCMODEL now has a full second derivative minimizer included the normal vibrational modes of a molecule may be computed. You will first be prompted for the name of a file to write the normal vibrational mode information, then a mass weighted hessian matrix will be generated, diagonalized and the vibrational modes will be written to the file. This file can be displayed using the Vibrate program (see below). MM3 does a reasonable job with vibrational frequencies while MMX does not give reasonable frequencies. 10.6 Mopac This command attempts to execute the program Mopac using as input the current structure. PCMODEL first attempts to find Mopac.exe in the current directory. If Mopac.exe is not located in the current directory and PCMODEL does not have any previous information about the location of Mopac.exe you will be prompted to provide a path to the executable file. Use the browse dialog box to locate and select the program. You should only need to do this the first time you run Mopac since the path information will be saved when you exit PCMODEL. Your version of Mopac must be capable of 76 reading a filename from the command line since we will be passing the filename to Mopac to execute. Serena Software markets a version of Mopac that does this. If you have obtained a copy of Mopac from other sources or you have generated it yourself you should check that this version can read the command line. After Mopac.exe is located, you will first be prompted for a name for a Mopac input file that will be generated, and then a dialog box for creating a Mopac format file will be presented. Either select from the standard options or enter the keywords you wish to use on the Keyword line. Mopac.exe will then be called with the filename a DOS type command window will be displayed and the calculations will be run. When the calculation is complete the DOS window will disappear and a new prompt will be displayed asking if you want to read the geometric output of the Mopac calculation. If you chose Yes, then a file dialog box will be presented for reading a Mopac Archive file. The filename will be “filename.arc”, that is the name you first created with the three letter extension ARC appended. Selecting this file will read in the new structure. If this file does not exist then the Mopac calculation failed and you should look at the file filename.out (or FOR006) to discover the source of the problem. 10.7 Ampac This command attempts to execute the program Ampac using as input the current structure. See the description given above for Mopac for instructions on running Ampac. 10.8 Gaussian PCMODEL can directly run Gaussian 03 (or Gaussian 98). In the Windows version the executable program to be run is g03.exe (not g03w.exe !!!!!).The Linux version is still setup to run G98 and not G03 (please contact us if this is a problem). In all versions a path to the Gaussian programs should be set before running Gaussian. (See the Windows documentation for setting the Path. In Linux read the Gaussian documentation for setting up the Gaussian environment variables) See the description for running Mopac for more details on finding the Gaussian executable and generating filenames. The dialog box for generating a Gaussian job file provides most of the standard options (see File Menu save section for more information about the dialog box), however additional options can be added by typing them on the keywords line. 10.9 Gamess PCMODEL can directly run Gamess. See the description for running Mopac for more details on finding the Gamess executable and generating filenames. The dialog box for generating a Gamess job file provides most of the standard options (see File Menu save section for more information about the dialog box), however additional options can be added by typing them on the keywords line. The Windows version of Gamess has a non-standard interface and while a job can be started from within Pcmodel we have not found a way to save the output (PC_Gamess sends the output to the screen by default). This is not a problem for the Macintosh or Linux versions of Gamess. 77 10.10 Orbitals This command executes the program Orbdraw which will display the molecular orbitals and electron densities that can be computed by the quantum chemistry programs Ampac, Mopac, Gaussian, Gamess and Jaguar. After the data file is selected the file is read and the number of atoms, orbitals and electrons are displayed in a dialog box. Next the orbital or density to display is selected from the View menu. The structure and selected orbital or density will be drawn. The entire image may be rotated by dragging the mouse with the left button depressed. The initial resolution for the display is 25x25x25 which gives a very crude picture but can be generated rapidly. A more detailed picture can be generated by increasing the resolution and threshold value. 10.11 Vibrations This command executes the program Vibrate which will display the normal vibrational modes that can be computed by the quantum chemistry programs Ampac, Mopac, Gaussian, Jaguar and PCMODEL. After the data file is selected and read a dialog box giving the number of atoms and vibrations of the structure will be presented then a stick figure of the vibrational spectrum will be displayed. A particular vibration can be displayed by either pointing to the line in the spectrum and clicking the mouse, or be selecting the vibration from the list of vibrations in the menu. Up to four vibrations may be displayed at once and the structures can be rotated. 10.12 GMMX This command initiates a conformational search on the current structure and up to four rings and fifty rotatable bonds can be searched at one time. There are many options available to control the search and they are discussed in the chapter on conformational searching. 10.13 Metropolis-MC This command initiates a Monte Carlo conformational search in internal coordinates. All bond lengths, angles and dihedrals are included in the search. 10.14 Vibrational Mode Search This command runs a conformational search that uses the low frequency vibrational modes as search directions based on the method of Kolossvary and Guida (Kolossvary and Guida, Journal of the American Chemical Society, 118:5011-5019). 78 10.15 Dynam DYNAM performs a molecular dynamics simulation using the leapfrog Verlet algorithm. Selecting this option brings up a Setup dialog box, through which several parameters of the simulation may be set. The time step for numerical integration (default 1 femtosecond) should never be larger than 5 fs (and the program may hang with this value). The next options are the initial temperature in K of the sample molecule and the surrounding bath (default for each is 300 K). The next option is the viscosity of the medium in cp (default of 0). The next parameter is the time constant for heat transfer (default value is 1, which results in transfer of energy from the bath to the sample). The final parameter is the equilibration time before the run is sampled. You may sample the run by clicking the Sample check box. The default sample time is 10fs. You will be asked to provide a file name for the run. At each sample point a structure will be written to the selected file. The run may be played back using the Movie option under the View menu option. Newton's equations of motion are used to calculate the position and velocity of all the atoms at each time step. This method can be used to add or remove kinetic energy from a molecule and to distribute the energy among various vibrational motions. Processes that occur on the pico- and femtosecond time scale can be studied. The initial structure should be minimized before starting the dynamics run. Initially the structure will be drawn overlaid on the screen along with the kinetic and potential energy at the current time. The screen is updated at each timestep. Remember that vibrations occur on the picosecond time scale and rotation about a bond, as in butane, may not be observed by this method. Dynamics has application to large structures where strain can be relieved by reducing van der Waals interactions. 10.16 Auto Dock The AUTO DOCK option takes two or more minimized structures and attempts to find the best interaction geometry. This is done using a simulated annealing algorithm. The basic series of steps is: 1. 2. 3. Evaluate the energy of the initial structures. Randomly translate and rotate the second structure about the first. Evaluate the energy of the new system. 79 4. If the energy is lower than that of the original system, accept the new structure and go to step 4. If the energy is higher than that of the original system, use the Metropolis algorithm to decide whether to accept the new structure. If the new structure passes then go to step 4, otherwise go back to the previous structure and then proceed to step 4. Increment the counter. When enough structures have been analyzed, lower the temperature which is used in the Metropolis algorithm. The net effect of this scheme is to accept fewer uphill energy steps, and drive the system to lower energies. Selecting the DOCK option brings up a dialog box to set the initial conditions of the calculation. The parameters are: XYZ displacement (default 1 Angstrom) Base angle (default 15 degrees) Start Temperature (default 3 kcal) Cooling decrement (default 0.1 kcal) Energy Change/Cycle (default 0.2 kcal) Stop on No Change (default 5 cycles) The xyz displacement is the distance the substructure will be moved in x, y or z times a random number. The base angle is the rotation angle to be used for rotating the substructure in x, y or z times a random number. The starting temperature is given in Kcal as are the cooling decrement and energy change per cycle. Clicking on OK brings up a dialog box into which the filename for saving the results should be written, then starts the calculation. When docking, the calculation may be aborted by hitting the ESC key on the keyboard. Since the simulated annealing procedure is stochastic, there can be no guarantee of success or even that two successive calculations will end up with the same structure. However, this method is superior to both manual and grid methods for docking studies. Trial and error is required, and starting from several different conformations can be useful. The structures to be docked should be located close together, since motion is limited to the sum of the diameter of the main structure, plus twice the diameter of the substructure plus 4 Å, even at the highest temperature. 10.17 Manual Dock The Manual Dock options allows the user to take two minimized structures and manuall move them about and evaluate the energy at each step. The entire ensemble can be rotated by dragging the mouse, and the individual molecules with the control panel. High energy interactions are shown in red as the structure is redrawn. 80 10.18 Batch The BATCH option allows the handling of multiple structure files without user intervention. There are a number of options including both calculations and file conversions. Selection of the BATCH option first brings up a file dialog box to get the name of a file containing multiple structures (see FILE OPEN for a detailed description of this dialog box). Any file format that supports multiple structures may be used. Next a dialog box to select the desired options is presented. The current options include energy minimization, computation of the surface area, volume or conversion of file type. One or more of these options can be selected. A FILE SAVE dialog is then presented to obtain the name and file type of the output file for saving output structures. The input file is then read and the number of structures is determined. A new dialog box is presented giving the number of structures, the default starting structure, and the default filenames for the output and summary files. The output file will be the name given in the FILE SAVE dialog and will contain the updated geometries after minimization or file conversion. The summary file will contain a summary of the minimization information including the MMX energy and the heat of formation, surface areas or volumes depending upon the options selected. The various fields of the dialog box may be edited to change the filenames and the default starting and ending structure numbers. Clicking on OK starts the calculations, which will run unattended until completion. The BATCH process can be stopped by selecting the STOP JOB button. The cursor will change from an hourglass to a pointer when the calculation is done. The bottom of the output window indicates the current structure number, and the total number of structures to be calculated so that progress in the BATCH process can be monitored. 10.19 Rot_E The Rot_E option evaluates the energy required to rotate about a given bond, using the rigid rotor approximation (meaning that the rotating ends are held rigid). The current structure should be minimized and the two atoms of the bond of interest should be SELECTed before ROT_E is selected. A dialog box appears, into which the step size (default 10) and total rotation (400) are entered. Clicking on OK starts the calculation. 81 The energy of the current structure is evaluated, then the specified bond is rotated by one step size increment and the energy is re-evaluated. This procedure is repeated until the total rotation value is reached, at which time a plot of energy vs. rotational angle is displayed. This plot may be printed via its FILE menu. the ROT_E method is only approximate since the energy is not minimized at each step of the calculation. This method is useful for a fast scan of the rotational energy minima, which can then be studied in more detail using the ROTATE_BOND and MINIMIZE options. A more accurate barrier may be obtained by using the ROTATE_BOND command under the EDIT menu to rotate the bond to a maximum value, then repeating the ROT_E calculation. 10.20 Dihedral Driver The DIHEDRAL_DRIVER option is an accurate, but more time consuming alternative to the ROT_E option. With the DIHEDRAL_DRIVER option, a particular dihedral angle is fixed at a specified value, and all the other degrees of freedom are allowed to relax. Up to two dihedral angles can be driven in one calculation. Before DIHEDRAL_DRIVER is chosen, the SELECT option from the TOOLS menu should be used to mark the 4 atoms of the bond of interest. When DIHEDRAL_DRIVER is chosen a dialog box will appear, displaying the selected atom numbers, along with the current value of the angle. Values for the starting angle, final angle and step size for the first angle must be entered. If two angles are to be driven, select "Get Second Angle". The dialog box will be dismissed, and the four atoms forming the second angle can be SELECTED. (The four atoms forming the first atom will be labeled with "d1".) Selecting DIHEDRAL_DRIVER again will cause the dialog box to reappear, with the data for the first and second angles present. The starting angle, final angle and step size for the second angle must be entered. When all the required information has been entered, click on CALCULATE. A new dialog box will appear for entering the filename for the output structures. During the calculation, the coordinates of each step, along with angle 1, angle 2 and the energy will be saved in a multiple structure file in either PCM or MMX format for later display and analysis. The one or two dihedral angles are rotated to their initial values and the energy of the structure is minimized, while holding the one or two angles fixed. When the energy of that structure is minimized, the second angle is incremented by its step size and the minimization is repeated. This procedure is repeated until the final angle of angle 2 is reached, then angle 2 is reset, angle 1 is stepped to a new angle and angle 2 is stepped through again. 82 dihedral driver dialog box. Choosing "last structure" (default) uses the previously minimized structure for the next calculation, while choosing "original structure" reads the original structure in, rotates the dihedrals to the specified angles, then calculates. The "last structure" option is faster if machine I/O is slow, but can have problems with very hindered structures where attached groups have a difficult time rotating past each other. The result of all these calculations is an n by m grid of points where n is total rotation of angle 1 divided by step size for angle 1, and m is the total rotation of angle 2 divided by step size of angle 2. The current limit on the grid size is 50 x 50. The DIHEDRAL_DRIVER method is more accurate than the ROT_E option since all other degrees of freedom are allow relaxed. However, it is more time consuming, and in molecules with more than three rotatable bonds one needs to ensure that other rotatable bonds have not rotated into a new energy minimum during the dihedral driver sequence. This often happens when attempting to generate Ramachandran plots of dipeptides. Again, the calculation may be aborted by pressing the ESC key. To reset the dihedral angle, use the RESET command under the MARK menu. 10.21 Relaxed Grid Search Some of the problems with dihedral driver calculations include the combinatorial explosion problem as more rotatable bonds are added and the failure to go to a minimum energy because of fixed dihedral angles. While the first problem can not be solved the second problem can with a relaxed grid search. The relaxed grid search uses the grid points as the starting points for an unrestrained minimization. Selection of Relaxed Grid Search first brings up a dialog box for entering the rotatable bonds of interest. The user can select the bonds or select all the rotatable bonds. Selection of OK starts the calculation. Initially all the rotatable bonds are set to 180 degrees and the energy is evaluated. The bonds are the step sequentially through 360 degree rotations and the structures are minimized. The program keeps track of the lowest energy found, removes duplicate structures and sorts the structures by energy at the end. The Relaxed Grid Search can handle many more bonds than the Dihedral Driver, but please remember that the combinatorial problem still exists and if you choose to rotate many bonds you will wait a long time for the results. 83 84 Chapter 11 Analyze Menu Surface Area Volume Connolly Calculate Surface area of molecule. Calculate Volume of molecule. Use the Connolly algorithms for calculating the Surface area and Volume of a molecule. Compare Compare different structures. Dihedral Map Display the results of dihedral driver calculations. Movie Replay of all the structures in a multiple structure file Dot Map Generate a dot map from a multi conformation file Multi Strucutre File Analyze a file containing multiple structures Assign Sym Assign point group symmetry. 11.1 Surface Area This option calculates the exposed surface area of the current molecular system. A stochastic algorithm is used which generates points on the surface randomly, determines if the point is exposed or not, and counts the number of exposed and unexposed points. A dialog box is used to set the number of points calculated for each atom (default 100), and the number of times the calculation is repeated (default 20). Since the method is stochastic the calculation is normally repeated several times and the average surface area values are reported. The calculation may be aborted by pressing the ESC key. When the calculation is complete, a window will appear with the total surface area, saturated area, unsaturated area and polar area. (The atom types of the atoms are used to divide the surface into non-polar, unsaturated non-polar and polar surface areas.) 11.2 Volume This option calculates the volume of the current molecular system. Both molecular volume (in cubic Å) and molar volume (in cubic cm) are reported. The calculation may be aborted by pressing the ESC key. 11.3 Connolly Surface This option calculates the surface area and volume of the current molecular system analytically using the algorithms published by M. Connolly (M. L. Connolly, "Analytical Molecular Surface Calculation", Journal of Applied Crystallography, 16, 548-558 (1983) and M. L. Connolly, "Computation of Molecular Volume", JACS, 107, 1118-1124 (1985 11.4 Compare This option allows the comparison of two or more structures. The main structure is, by definition, the structure with the lowest substructure number. If only one structure 85 is present when the Compare option is first selected, the structure is redrawn colored by substructure and a dialog box is displayed so that a comparison structure can be read in. If two or more substructures are present when COMPARE is selected, the structures are redisplayed colored by substructure and the compare dialog box is then displayed. Comparisons can be done an all atoms (default), heavy atoms only, or selected atoms only. In order to use the Selected atoms option, the atoms must be SELECTed using the SELECT button from the TOOLS menu before the COMPARE option is chosen. The atoms may be marked in any order, but the calculations will match the first selected atom of one structure with the first selected atom in the second structure, and so on. Alternatively, one atom in the first structure may be selected, followed by the atom to be matched to it in the second structure. The other option in this dialog box are: Calculate - starts a least squares calculation which attempts to minimize the differences in the positions of the atoms being compared. The results of the calculation will be given in the Compare window. The table of results will include 3 columns - atom in structure 1, corresponding atom in structure 2, and distance between them in angstroms. At the bottom of the table are the average difference between the distances, and then the root mean square difference in the distance. If the output is too large to fit in the window, the window can be scrolled. The structures will be drawn in the Structure window overlapped with red lines connecting the atoms that are being compared. If the structures overlap well, the red lines may not be visible. Reset - clears the comparison arrays and removes the red lines between comparison atoms from the drawing. This button is essentially used only for cleaning up the screen. Next Structure - allows reading in another structure for comparison. If two or more structures are currently present, all but the main comparison structure will be hidden. a file dialog box will be presented for selecting the desired structure file, the structure will be read in and displayed to the right of the current structure, colored in the appropriate substructure color. Hide - makes all the comparison structures invisible. This is useful to keep the screen from becoming cluttered when many structures are being compared. Show All - makes all comparison structures visible. This is useful to display several structures that have been compared. Cancel - dismisses the Compare dialog box. All comparison structures are deleted, and the main structure is re-displayed. It is necessary to erase all the comparison structures since they occupy the same coordinates as the main structure (if the comparison has been successful), and would cause any subsequent molecular mechanics to fail. 86 11.5 Dihedral Map This option allows redisplay of the results of a prior dihedral driver calculation. A dialog box is presented prompting for the filename of the saved calculation. The file is then read and a one angle or two angle plot is presented. See the FILE OPEN command for a detailed discussion of the use of the file dialog box, and the DIHEDRAL_DRIVER option in the ANALYZE menu for a full discussion of dihedral driver calculations. 11.6 Movie This option reads a multiple structure file and shows all the structures in sequence. The file formats currently supported include PCM, MMX, Gaussian output and Cambridge Structural Database. PCM type multiple structure files are often generated during a dynamics run, or part of a GMMX search. Thus the results of a dynamics run can be replayed using this options. Another use of this option is to view the results of a Gaussian reaction coordinate scan. You will first be asked to select a file for play. The options in this dialog box are: Play – Plays the movie. Step – Steps through the file one structure at a time. Loop – Continuously plays the movie. Stop – Stops the Play or Loop. Exit - Exits the dialog box and returns to PCMODEL. The total number of structures in the file (5 in the illustration) and the current structure number (1) will be displayed. The track bar reports the progress of the movie but does not respond to clicks of the mouse. 11.7 Dot Map This option reads in a file from a GMMX search, compares a selected set of atoms and orients each structure to overly the first structure, then plots the position of a selected atom from each structure relative to the original structure. The result is a new structure containing the position of every place where the selected ‘dot’ atom can visit in the various conformations. See Midland, M.M.; Plumet, J.; Okamura, W.H. “Effect of C20 Stereochemistry on the Conformational Profile of the Side Chains of Vitamin D Analogs,” Bioorganic and Med. Chem. Letters 1993, 3, 87 1799-1804. for an application in the vitamin-D field. After selecting Dot Map, a file-read dialog box will appear. Usually you will want to use the first structure for the comparison. Next enter the atom numbers for the comparison overlay. This can be done by either typing in the numbers separated by a space or comma, or by using the Sel-Atm option from the Draw Tools. If Sel-Atm is used, click on Update to fill in the edit box. Next select the atom for the dot. This can be done by entering an atom number or by reselecting Sel-Atm, clicking on the appropriate atom and then on Update. The dots will look bigger on the screen then in the print out. Do not add hydrogens to the resulting structure, particularly if the dot atom is an oxygen or nitrogen. An example of a dot map is shown below. 11.8 MultiStructure Multi structure/conformation files can be analyzed. There are three main options- View Structures, Analyze Structures and Compare and Extract Structures. View Structures. The View structures option provides a quick way to step through a file and look at individual conformations. A scrolling list of all the structures in the file is shown and the file is displayed when selected from the list. This is very similar to a standard file open, but the scrolling dialog box is not dismissed and no questions are asked. Analyze Structures. This option allows you to perform query operations (distance, angles etc) as well as surface area, volume and box size calculations on a multi structure file. Clicking on the Query buttons will provide a dialog box for editing the query list. Queries may be entered by using the Query button from the DrawTools and then hitting the Update Queries button. If the multi structure file is from a GMMX search, then the energy information will be read from the file and used to calculate a Boltzmann distribution for the queries. You will be asked to give the name of an output summary file. 88 Compare and Extract Structures. This option allows you to compare all structures in a file or in two files, To extract all structures which match a query or to extract a set of structure from a file. For example you may want to retrieve all structures from a GMMX search which have two atoms 5.1+/-0.3 A apart 11.9 Assign Symmetry This option attempts to assign the point group of the current structure using the cartesian coordinates. 89 90 Chapter 12 Substr Menu This menu contains the following commands: Read Create Move Connect Fuse Erase Show Dummy Don't minimize Read a structure file and label the structure as a substructure. Label the selected structure as a substructure Moves the selected substructure. Connect two structures. Fuse two rings. Removes the selected substructure from existence. Display any dummy atoms in current structures. Marks the selected substructure so that it will not be minimized in a molecular mechanics calculation. Substructures are a method for naming and manipulating individual molecules. By default any structure read into PCMODEL using the OPEN command, or any structure drawn in the Structure window is initially assigned to substructure number zero. Several molecules may be drawn in the Structure window, but they all belong to substructure zero and all will be moved, erased or minimized together. In order to manipulate the structures individually it is necessary to mark them as substructures. The commands available in the Substructure Menu provide all the facilities necessary for handling substructures. 12.1 Read The READ command reads a structure file into PCMODEL, marks it with a unique substructure number and displays it to the right of the current structure. The current structure is not erased. A file open dialog box is used for obtaining the filename, filetype and path (see the FILE OPEN command for a detailed description of this dialog box). Up to thirty two substructures may be created at one time in PCMODEL. 12.2 Create The CREATE command marks a structure present in the Structure window as a substructure. Before choosing CREATE, at least one atom in the structure must have been marked with the SELECT button from the TOOLS menu. When the CREATE command is chosen, a dialog box appears requesting a name for the substructure. This name is associated with the substructure and can be used with the MOVE, ERASE, HIDE and DON'T MINIMIZE commands. 12.3 Move The MOVE command allows one substructure to be translated and or rotated with respect to all the other structures. There are several methods for selecting the substructure 91 to move. One method is to use the SELECT button on the TOOLS menu to mark an atom in the substruture to be moved before chosing MOVE. Alternatively, if no atoms have been selected when the MOVE command is chosen, a dialog box will be presented listing all substructures by name, and the substructure to be moved can be chosen by selecting its name from the list with either the left mouse button or the up/down arrow keys. After a substructure has been selected, click on OK, and the Control Panel dialog box will appear. The translate and rotate controls will now only work on the selected substructure. Rotation will be about the center of the selected substructure. To change the substructure being moved, simply select an atom in another substructure. The Control Panel controls will now operate on that substructure. Complex docking can be accomplished by translation and rotation of selected substructures. To rotate the entire collection of molecules as a unit it is necessary to Exit the Control Panel dialog box, and then chose the CONTROL_PANEL option from the VIEW menu. 12.4 Connect The Connect command connects two structures. First, SELECT the two hydrogens to be removed to make the new bond (using the SELECT button in the TOOLS men). The hydrogens will be removed and a new bond will be drawn between the two heavy atoms that the hydrogens were attached to. Please see Chapter 3, Tutorials, for a step by step description of connecting two molecules. 12.5 Fuse The Fuse command fuses two rings. First, SELECT the two atoms in the first ring and then two atoms in the second ring. The two atoms in the second ring will be removed and the rings will be fused. The two rings should be recognized as separate molecules. If you are uncertain use the Labels option from the View Menu and select Color by Substructure. If the two rings are not different colors then they are not recognized as separate structures. To make the two rings into separate structures select one atom in one ring and use the Substructure Create option described above. 12.6 Erase The ERASE command allows a substructure to be erased (deleted from existance). As with SUBST MOVE, any atom in the substructure to be deleted may be SELECTed before chosing ERASE, or if none are selected a dialog box will list the possible substructures. There is no prompt for confirmation. Once the structure is deleted it can not be recovered. 12.7 Show Dummy The SHOW DUMMY commands redraws the structure with all dummy atoms (atom type 60 in MMX) shown with gray dots over the atom. Dummy atoms can be placed in a structure using the Dummy Atom type from the periodic table. Dummy atoms have the same properties as hydrogens and can thus be minimized, but they are not 92 removed by HAD. The main purpose of Dummy atoms is to serve as place holders for points of connection while building polymers or other large structures. See the Tutorial Chapter of the use of dummy atoms in building poly-stryene. 12.8 Don't Minimize The DON'T MINIMIZE command marks a substructure so that it will be ignored during an energy minimization. This is a useful procedure when studying interactions between surfaces and molecules, in which the interactions between the surface and the molecules are of interest, but minimizing the surface would not be practical. This allows building surfaces that are only two or three atoms deep, and thus would not maintain their geometry if minimized, reading the surfaces into PCMODEL and then studing the interaction of these surfaces with various molecules. As with SUBST MOVE, any atom in the substructure to be deleted may be SELECTed before chosing DON'T MINIMIZE, or if none are selected a dialog box will list the possible substructures. 93 94 Chapter 13 Mark Menu This menu contains commands that H Bonds Pi Atoms Metal Coord TS_BondOrders Fix Distance Fix Angle Fix Torsions Reset Hydrogen Bonds Pi atoms. Set electron count, charge and coordination of metal atoms. Set the bond orders for transition state bonds. Fix a distance between any two atoms-up to 10 pairs Fix an angle. Up to 10; Fix a dihedral angle Reset any of the above and also substructure membership. 13.1 H_Bonds The MMX force field contains an extra term to correct deficiencies (in the original MM2 force field) in describing hydrogen bonds. This term is turned on or off depending upon whether the hydrogen bonds are marked. The default is to automatically mark hydrogen bonds and to turn on the extra term in the force field. If the hydrogen bond marking is turned off using the Reset option (see below), then the H_Bond option is used to turn on the hydrogen bond term again. Hydrogen bonds are shown in red between a donor hydrogen and acceptor atom when the distance between the two is less than 2.10 angstroms. 13.2 Pi Atoms The MM2 and MM3 force field only contains one atom type to describe alkenes (atom type 2), which is used to describe all types of unsaturation. The default parameters for atom type 2 are set to reproduce the geometry of an isolated double bond, such as ethylene, and will not accurately represent the geometry or energy of a conjugated system such as butadiene or benzene. The solution to this problem is to do a simple pi vescf calculation on conjugated systems. This calculation gives the bond orders of all the bonds in the conjugated system, and these bond orders are used to adjust the stretching and torsional parameters for those atoms in the conjugated system. The pi atom marking is used to tell PCMODEL which atoms belong to the conjugated system and that a pi calculation should be done. Selecting the Pi atom marking will automatically mark all conjugated atoms. Reset is used to unmark the atoms. When Pi atoms are marked and minimize is selected PCMODEL will first do a pi calculation on the conjugated system, the parameters will be adjusted and then 15 iterations of geometry optimization will be done. A pi calculation is then done on the updated geometry, the parameters are again adjusted, and a complete minimization is done. When the minimization is complete another pi calculation is done, followed by another minimization. The minimization ends when no change in the geometry is observed after a pi calculation. 95 13.3 Metal Coordination The Metal Coord option is used for coordinating lone pairs and pi systems to a metal atom, setting the electron count and geometry of a metal, and setting the charge on the metal. The metal atom of interest and any coordinated atoms must first be selected using the SELECT button on the TOOLS menu. After selecting Metal Coord a dialog box will be presented showing the metal atom symbol, the current charge if any, and a set of radiobuttons describing the electron count and geometry. The force field model was designed with no charges on the metal atoms (default charge is 0). Setting a charge will turn on electrostatic interactions with other atoms and should be treated with caution. The electrostatic model within molecular mechanics is not well defined or well tested, but it is known that formal charges do not work well. You should check your calculations against known compounds as you make modifications. If the Metal Coord option is not used, all metals are assumed to be coordinately saturated, and there will be no attractive potential between the metal and the lone pair or p-orbitals of ligands which were not explicitly bonded during the DRAW phase of the input. Atoms coordinated to the metal will be shown with a dotted line between the atom and the metal. 13.4 TS_Bond Orders If transition state atom types are used, their bond orders must be set before a minimization can be done. When the TS_BondOrders option is selected a dialog box appears listing the transition state bonds found and the current bond orders (if any are known). The bond orders should be entered in the appropriate edit boxes. This data will be written to the structure file when the file is saved. 13.5 Fix_Distances The Fix_Distances option is used to fix the distance between two atoms, and up to ten pairs can be fixed at one time. The two atoms whose distance is to be fixed should be selected using the SELECT button on the TOOLS menu, then Fix_Distances can be selected from the MARK menu. A dialog box will appear listing the two atoms, the current distance and two edit boxes, one for the distance to fix at, and the other for a force constant (default 5.0 mdyne/angstrom ). The distance is fixed by creating a bond between the two atoms with the default distance set at the fixed distance, and with a force constant input. The default force constant works for most cases. Fixed distances can be combined with energy minimization or dynamics to build large structures with specific interactions, for example, folded peptides (where the fixed distances come from NMR experiments). 96 13.6 Fix Angle The Fix Angle option is used to fix the angle made by three atoms and up to ten angles can be fixed at one time. The three atoms of the angle should be selected first using the Select button, and then Fix Angle from the Mark menu. A dialog box will appear giving the atom numbers of the atoms of the angle, the current angle and edit boxes for the angle to fix at and the force constant to use. 13.7 Fix_Torsions The Fix_Torsions options is used to fix up to two dihedral angles. The four atoms defining the dihedral angle must first be selected using the SELECT button in the TOOLS menu. The Fix_Torsion option will then present a dialog box listing the four atoms, the current angle, and an edit box for entering the angle to fix at. The routines used for fixing a torsion are the same as those used for the dihedral driver and are limited to two dihedral angles at one time. 13.8 Reset The Reset option brings up a dialog box which allows resetting all the options given above, and also substructure membership. 97 98 Chapter 14 Options Menu This menu contains commands that Printout Dielc DPDP Minimizer MMX_PI Options Added Constants Standard Constants Stereo Pluto VDW Surface Dot Surface Sets the amount of output in the file PCMOD.OUT. Resets the dielectric constant. Switch between dipole/dipole and electrostatic calc. Control which minimizer to user. Set options for Pi calculations. Allows the addition of user defined constants Forces the use of the default data set Changes the direction of rotation of stereo display. Set Pluto options Set VDW display options Set Dot Surface display options. 14.1 Printout The PRINTOUT option sets the level of information written to PCMOD.OUT. The default is to write a minimal output file which lists that atomic charges, any generalized constants used and the initial and final energies for a calculation. Full printout gives a complete list of all interactions used in the calculation of the final energy. Each bend, stretch, torsion, VDW interaction and charge-charge interaction is listed with constants used, current geometry and the energy contribution from that item. A full printout can be quite long. The current option (Full or Min-imal) is indicated in the Output window. 14.2 Dielc The DIELC option sets the dielectric constant which has a default of 1.5. It is rare for increases in DIELC to reproduce the properties of molecules in higher dielectric solvents, so this should be used with great care. If a negative value for DIELC is input, then the charge-charge interaction will be calculated with a distance-dependent dielectric constant (Dielc = f(Rij )), an option that is used successfully in the AMBER program when attempting to model the effect of a polar solvent or lack of counterions. Setting Dielc to -1. will adversely effect calculations done with dipole-dipole interactions. 14.3 DPDP The DPDP option allows choice of either dipole-dipole or electrostatic calculations. The default in PCMODEL is to use electrostatic calculations with the charges being calculated from the default bond moments. This is a more general procedure and allows incorporation of charged species. However, the MM2 force field 99 was originally developed with the dipole dipole method. The charges for the electrostatic calculations are, in most cases, derived from the bond dipoles programmed into MM2 for the bond dipole option, although heteroatom pi systems will also contribute charges. The default electrostatic calculations use the MM2 charges but also include the dielectric constant in the denominator of the energy expression. Electrostatic calculations should be used with atoms having charges (e.g., N+, C-) and they will also allow the halogens to be considered as ions if they are not directly bonded to any other atom. The only reason to use DP-DP is to compare a calculation to an MM2-like calculation. 14.4 Minimizer This options controls the default actions of the minimizer. PCMODEL now includes a first derivative minimization method, BFGS, and both truncated NewtonRaphson and full Newton-Raphson second derivative minimization methods. The default behaviour is to do a first derivative minimization until the gradient falls below 1, and then a second derivative minimization until the gradient falls below 0.0001. This dialog box allows you to switch to a first derivative only minimization, second derivative only method or to the mixed method. While the mixed method appears to be the most robust method for general use, there are times when the path taken through conformational space is dependent upon the choice of minimizer. 14.5 MMX_PI Calculation Options This option allows setting a number of options for the pi calculation. The choices are: RHF or UHF Choose between Restricted Hartree Fock and Unrestricted HF calculation. For closed shell molecules with all the electrons paired the RHF option should be used. The UHF option is used for species with unpaired electrons (monoradicals, diradicals etc.) or for higher spin states. Mult Set the multiplicity of the system. The default is 1 for a singlet state. Huckel or Full SCF Set the type of the initial pi calculation. The default is to do a simple Huckel calculation which ignores the geometry of the pi system in determining the bond orders. This method is preferred when the starting geometry is poor. The Full SCF uses the geometry of the pi system in determining the bond orders and will give better bond orders if the starting geometry is close to the final geometry. 100 Non-Planar or Planar Pi System- This tells PCMODEL whether the entire pi system is planar or non-planar. The default is to assume a non-planar pi system and check for non-planarity. Use the Planar option only if the entire pi system is co-planar. All of these options are reset when a structure is erased. 14.6 Added Constants The Added CONSTANTS option forces allows the use of a file of user defined constants to be used in addition to or as replacements for the standard constants. The user is prompted for the name of the added constants file, which must use the same format as the standard constants file. PCMODEL checks as the added constants are read and replaces the standard constants if one exists or adds the new constant to the bottom of the parameter list if no previous constant has been defined. To return to the standard constants use the Standard Constants button below. 14.7 Standard Constants The STANDARD CONSTANTS option forces PCMODEL to use the default constants. All parameter arrays are set to zero and the default parameter files, mmxconst.prm is read 14.8 Stereo The Stereo option sets the direction of rotation for the stereo display. The options are to rotate the two structures inward (cross eyed display) or outward (wall eyed display, default). The selecteds option remains in effect until changed. 14.9 Pluto Choosing this option brings up the following dialog box: Ang1 and Ang2 - Control the position of the light source. Shade – Controls the density of the shade lines, lower number gives more lines. Ball_Stick or CPK – Produces a ball and stick structure or a space-filling structure. Bond Taper – A higher number will give a greater perspective taper to bonds. Bond Radius – Controls how wide the bonds are when drawn. A large number gives wider bonds. Bond Lines – How many lines are 101 drawn per bond. The default values are given in the example dialog box. 14.10 Vdw Surface Upon choosing this option the following dialog box appears: The atoms to be displayed in this manner can be all atoms, heavy atoms only or selected atoms only. In order to use the Selected-atoms option, the atoms must be SELECTed using the SELECT button from the TOOLS menu before the CPK option is chosen. The radius for the CPK model can be varied from the van der Waals radius (1.0, default) down to 0.65 (the .20 ball and stick option has been removed). The “color by” option has not been implemented. The CPK model continues as the default display until either the STICK FIGURE option is chosen, or the CPK_Surface dialog box is brought up and canceled. The CPK models can be rotated and translated. CPK models, dot surfaces and Ribbon diagrams can all be displayed at the same time. 14.11 Dot Surface Choosing this option brings up the following dialog box: The dot surface is generated using the Lee and Richards algorithm and two different radii are available - the van der waals radius (default) or a water surface (van der waals + 1.4 Å). The CHARGE option uses the van der waals radius and colors the surface by charge, with redder colors representing positive charge and bluer colors representing more negative charges. White is used for neutral atoms. 102 The atoms to be displayed in this manner can be all atoms or selected atoms only. In order to use the Selected atoms option, the atoms must be SELECTed using the SELECT button from the TOOLS menu before the DOT_SURFACE option is chosen. The Dot Spacing option controls the number of dots displayed on the surface. A closer spacing gives more dots, but takes longer to draw and manipulate (rotate and translate). The dot surface model continues as the default display until either the STICK_FIGURE option is selected, or the DOT_SURFACE dialog box is brought up and canceled. CPK models, dot surfaces and Ribbon diagrams can all be displayed at the same time. 103 104 15 The MMX Force Field 15.1 The MMX Force Field The MMX force field embodies many years of work by J.J. Gajewski and K.E. Gilbert to extend and improve upon the MM2 force field of N. L. Allinger. The starting point for MMX was the MM2(77) program of Allinger. To this was added the VESCF pi routines from MMPI, and the concept of generalized parameters from C. Still. The goal of this work was to be able to treat more compounds of interest to synthetic and mechanistic organic chemists. For example, such functional groups as radical, cations and anions are not handled in MM2. The current version of MMX recognizes nearly 60 different atom types including radicals, anions, cations, transition metals and transition state atoms. The table below lists the atom types, symbols and a brief description. ATOM TYPE NUMBERS - MM2/MMX Type Symbol 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 C C C C H O O N N N F Cl Br I S S+ S S Si LP H C H H P Description Carbon, SP3 Carbon, SP2 (Alkene) Carbon, SP2 (Carbonyl) Carbon, SP Hydrogen (note special types 21,23,24,28 below) Oxygen (singly bonded) Oxygen (doubly bonded) Nitrogen, SP3 Nitrogen, SP2 of enamines and amides Nitrogen, SP Fluorine Chlorine Bromine Iodine Sulfide (-S-) Sulfonium (>S-+), NOT sulfoxide! Sulfoxide-use double bond to O. Sulfone-use double bonds to O. Silane Lone pair (:) Hydrogen, Hydroxyl (-OH) Carbon, Cyclopropane Hydrogen, Amine (NH) Hydrogen, Carboxylic acid (COOH) Phosphorus [PRELIMINARY] 105 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 B B H C. C+ Ge Sn Pb Se Te D N S Se Ar Boron (trigonal) Boron (tetrahedral) Hydrogen (enol) C Radical Carbonium ion Germanium Tin Lead Selenium Tellurium Deuterium Nitrogen SP2 of Imine Thion sulfur Selenoxide Se Aromatic Carbon (1.40Å bonds between 40-40) (Use this atom type only when conjugation effects are not a concern. If conjugation effects are important, use and mark it as a pi atom.) N+ Ammonium nitrogen O- Oxy anion TS Boron Not Used TS Hydrogen Onium ion, also metal bound carbon monoxide Pentavalent phosphorous Carbanion Transition State (TS) Carbon Transition State (TS) Carbon TS Trigonal carbon bonds to C* TS Pentavalent carbon bonds C*, O#, and I% TS Oxygen bonds to C# and C% TS Iodine bonds to C% in SN2 TS Nitrogen bonds to C# Cyclobutane carbon as in MM3 Cyclobutene carbon as in MM3 WILD CARD 2 WILD CARD 3 Spherical water normal carbon 41 N+ 42 O43 B# 44 xx 45 H* 46 O+ 47 P5 48 C49 C* 50 C# 51 C$ 52 C% 53 O# 54 I% 55 N# 56 C 57 C 58 Z1 59 Z2 60 Aq ???? other types Parameters were developed by standard methods, using literature values, interpolated values from known parameters, or chemical intuition, followed by comparison to experimental data for geometries and heats of formation. The complete parameter set is found in the data file mmxconst.prm.. 106 15.2 Minimization with PCMODEL (hints) Whenever a molecule is minimized in PCMODEL, an Output window displays the results of the calculation. The upper portion of the Output window displays the total energy, as well as a breakdown by component, dipole moment, heat of formation (Hf) and Strain Energy (SE). The components of the energy are Str (stretching), Bnd (bending), StrBnd (stretch-bend cross term), Tor (torsion), VdW (Van der Waal interactions), and QQ (charge-charge electrostatic interaction). The lower portion of the Ouptut window indicates the dielectric constant that was used in the calculation, whether default or added constants were used, and the current level of printer output (default is minimal). The MMX energy has a correction for 1-3 electrostatic interactions when two non-zero charge atoms are attached to a sp3 carbon. This correction is not made with any other central atom and can be a source of error. If there are no cations or anions in the structure or no charged pi systems, a single point calculation using the DP-DP interaction should give a better energy for polar molecules. A major problem in minimizing structures draw without a template is that hydrogens and lone pairs are often forced into inappropriate positions, resulting in high energy structures. It is a good idea delete then re-add hydrogens (by pressing H/AD on the TOOLS menu twice) then reminimize. Also, for large structures reminimizing is recommended (select MINIMIZE again) to make sure the structure is fully converged. Since minimization is quite time-consuming with large molecules, it is often economical to minimize the structure without added hydrogens to get the threedimensional structure approximately right prior to adding hydrogens and doing a final minimization. PCMODEL has access to a number of generalized force field parameters (torsional potentials dependent only on the two central atoms) to which the program defaults if no standard MM2 parameters are available. These parameters are not optimal and energies produced with them should be considered accordingly. However, the geometries can be considered fairly accurate. The use of generalized parameters is always noted in the output file PCMOD.OUT. All of the parameters for ligands directly bonded to a metal or for ligands coordinated to a metal assume no charge on the metal. A charge on the metal can be set using the Metal_Coord choice in the Mark Menu. This option should be used only if the electrostatic attraction between ligands and a metal are to be employed and not formal bonding or coordination via the Metal_coord option. Formal charges are not a good representation of charge distribution in metal complexes. The heat of formation calculation will be marked as INC (incomplete) if some bond parameters are missing. The pi contribution to the heat of formation depends on whether the default point charges or the bond dipole interaction are used (NDC=0). The default uses atom contributions and the pi energy calculated; if NDC=0, a bond contribution scheme based on pi order is used. The list of bond types handled by the former option is incomplete relative to the latter; however there is no warning that this is the case. It is important to note that the MMX energy resulting form a minimization with a pi calculation does not contain the potential energy of the pi system. So, a comparison of MMX energies for isomeric pi systems is invalid, just as a comparison of MMX energies is invalid for structural isomers. A comparison of the heats of formation, on the 107 other hand, is appropriate. The only circumstances where MMX energies may be compared directly is with conformers or diastereomers. 15.3 Transition State Atoms Transition states can be modeled using PCMODEL. The eleven transition state bonds that are recognized are: C* - C* C# - C# C - H* C* - H* C# - B# C* - C$ C# - O# C* - C% C% - I% C% - O# C# - N# e.g. forming bonds in Diels Alder rxn or in Cope rear. e.g. forming bonds in Diels Alder or breaking bonds in Cope. e.g. allylic C-H bond in ene reaction. e.g. forming H-C bond in ene reaction or hydroboration. e.g. forming B-C bond in hydroboration. e.g. forming bond in addition of nitrile oxide sp C to sp2 C. e.g. breaking bond in Claisen rearrangement. e.g. carbon nucleophile in SN2. e.g. leaving group bond in SN2. e.g. oxygen nucleophile in SN2. e.g. breaking bond in an Aza Cope rearrangement. These transition state bonds are fractional. The user must input a bond order for each when requested by PCMODEL. Note that Diels Alder transition states are "early" and have both bond orders roughly 0.3 for symmetrical addends. Bond orders of 0.3 will mimic the nitrile oxide addition to ethylene transition state calculated by Houk (make sure that the nitrogen has a double bond so that it is a type 37 atom). Cope transition state bond orders depend on substitution, as do all of these as revealed by secondary deuterium isotope effect studies. That is why the user is in complete control of the transition state bond orders. For other pi atoms in pericyclic transition states use C.s, the radical carbons, eg. for C2 and C5 of 1,5-hexadienes in the Cope transition state or for C2 and C3 of butadiene in the Diels-Alder transition state. NOTE: You CANNOT do a Pi calculation on C* or C#; Further, the bonds between the C.s in the transition state are fixed at 1.40 Å and have k=7.0. PCMODEL generates a set of transition state atom parameters from the fraction bond input by the user. These parameters for C* and C# force 90 degree angles between C*1 C*2 and any other atom as the fractional bond order approaches 0. This angle will spread to 109 degrees as the fractional bond order approaches 1, as will C#-O#. The parameters generated for B# additions attempt to mimic the acute angle between B# and C#-C* with appropriate hydrogen angles and distances. The angle at C$ of a C$-C* starts at 180 degrees for no bond and goes to 120 when the bond order approaches 1. The angles of the bonds to C% start at 109 with C%-I% bond order of 1 and an incoming nucleophile bond order of 0.; they go to 120 when both bond orders to C% are equal, and then return to 109 as the incoming nucleophile -C% bond order approaches 1 and the C%-I% bond order approaches 0. 108 The transition state bond natural bond lengths are determined by the input bond orders according to Badger's Rule cast in Pauling bond order terms: distance = distance of fully formed bond - 0.6•ln (bond order). force constant = force constant for fully formed bond * bond order. The constant 0.6 is twice as large as the Pauling constant for bond orders greater than 1. This value is used because it reproduces the structure of the Diels-Alder transition state calculated by Houk from 3-21G basis set, if the kinetic isotope effects determined at Indiana on the Diels- Alder reaction are used as input bond orders. 15.4 Pi Calculations The constants in PCMODEL will reproduce acids, esters, amides, eneamines, vinyl ethers, carboxylates, nitro groups, alpha, beta unsaturated aldehydes and ketones, allyl cations, anions, and radicals NOT conjugated with a pi system without having to do a pi calculation on these specific functional groups. However, adjacent pi systems will not "experience" the pi electron effect of these groups unless they are included in a pi calculation. Any diene or material with more than four conjugated pi electron should be subjected to a pi calculation (See hints on specific atoms below). If a pi calculation is done with these atoms, non-delocalized constants are used and are adjusted by the bond orders. Pi calculations must be done on other delocalized moieties such as alpha, beta unsaturated imines, nitriles, etc. The pi calculation can be done as either a closed shell or open shell type so that monoradicals are handled reasonably unlike earlier versions of the MM2 force field such as is found in MMX87, MMPMI, MMP2, or MMP1. The pi portion of the code, which is the R.D. Brown VESCF procedure, has been checked against MMP1 (QCPE 318). 15.4.1 Pi Atoms The pi atoms treated originally are: C sp2 (type 2) C (carbonyl carbon type 3) C sp (type 4) O sp3 (type 6) O (carbonyl oxygen type 7) N (amide-like type 9) N (nitrile type 10). The additional new pi atoms are: C. C+ N+ O- (type 29) (type 30) (ammo-& immonium type 41) (type 42) 109 N C- (imine type 37) (type 48). MMP1 and MMP2 will not recognize any of these atoms. Pi calculations cannot be performed on third row elements like S or P, nor can any of the halogens be included. Compounds with twisted or pyramidalized monoolefins should be submitted to a pi calculation for comparison purposes. 15.4.2 Heat of Formation of Pi Systems The contribution of the pi system to the heat of formation depends on pi bond orders. First the number of double bonds in a non-charge-separated valence bond structure is determined from the number of filled MOs minus the appropriate number of electrons from any type 6, 7, 9, 29, 42, and 48 atom. The number of each type of double bond is multiplied by the contribution each makes to the heat of formation as described in MM2, e.g. 22.8 for each C=C, -24.5 for each C=O, 31.0 for each C=N, etc. Bonds involving a type 6, 9, 29, 30, 42, or 48 atom have a contribution of a constant which is roughly that if the electron(s) were not delocalized, e.g. 0. for 03-09, -16.7 for 02-06 and for 03-06, 12. for 02-48, etc. In MMX for pi atom pairs of the latter description, the pi bond order multiplies a negative constant unique to each so as to decrement the heat of formation; this seems reasonable-higher bond order, lower energy. However, for pi atom pairs not in the latter category, a pi bond order between 0.4 and 0.85 will decrement the heat of formation by a constant characteristic of the atom pair; the decrement falls of as rho2 when rho is less than 0.4 and as (1-rho)2 when rho is greater than 0.85. It is this function which allowed the use of bond orders for the heat of formation calculation; however, it does poorly for larger >C8 carbocyclic pi systems. The calculation of the heat of formation of the pi system depends on whether only type 2 (olefinic), type 29 (radical), type 30 (cation), and type 48 (carbanion) carbons are present or (& heteroatoms without a charged atom or C.) or whether N+, O- or C.,C+, or C- and heteroatoms are present. In the former cases with just trigonal carbon, the sum of pi bonds multiplies 90.2 kcal/m (the strength of a strainless Csp2-Csp2 bond). To this is added the compression energy using 1.51 as the strain free value ( the quadratic constant is 517 kcal/ang*2). To this is added the Pople pi energy (a negative quantity); then the contribution of each pi atom to the pi portion of the heat of formation is added (these values are 92.8 kcal/m for a pi atom attached to one other pi atom; 141.95 for a pi atom attached to two others; and 189.0 for a pi atom attached to three others). A similar parameterization applies to other cases within the first category. In the latter cases, each C=C contributes 11.2 kcal/m to the heat of form.; then the compression energy is calculated using 400 kcal/m as the constant. Finally, the difference in the total bond order of the pi system relative to that of the number of classical pi bonds is multiplied by 35 kcal/mol to obtain the pi stabilization. The contribution from the other bonds is similar to that in MMPMI where the bond orders key the contributions to the heat of formation. Generally the heats of formation are good to 2 kcal/mol, but it is unclear where large deviations might occur. 110 15.5 Transition Metals Note that many basic atoms can be docked (not attached with a bond that appears in the connected and attached atom lists) with their lone pair to a metal. Alternatively, atoms can be attached with a bond replacing the lone pair, and despite the increase in positive charge at the atom, the neutral atom types above should be used, e.g. M-N tetravalent (use type 8 not type 41). TYPES of BONDS to Metals that MMX will recognize (Use the Atom Types option in the LABELS of the VIEW Menu to make sure that the proper atom types are used): to NITROGEN/ M <- :N- type 8 \ amino, can dock for automatic Hs & lps or specify all four bonds including Hs (no lp). M - N< type 9 pair amido, to coordinately saturated M, specify 0944 bond. no lone M - N-C= type 9 pair \ M <-:Nsp type 1 recognizes amido, N next to unsaturated carbon, specify 0944 bond, no lone on N. nitrile or nitrogen coordinate or specify all bonds (no lp), MMX this relative to nitride below. M N: sp type 10 nitride M = N+< type 41 amido, to coordinately unsaturated M, specify 4144 bond. M <-:N= type 37 \ imino, coordination-requires docking; or specify all four bonds including metal. M -N:= type 37 bond, imido, to coordinately saturated M, eg. bent nitrosyl, specify 3744 leave lone pair on N. M = N+= type 41 4144 group. M - N: sp type 10 imido, to coordinately unsaturated M, eg. linear nitrosyl, specify bond, MMX will recognize the difference between this and amido to OXYGENM - O - R type 6 two lone pairs on O, coordinately sat'd metal. M = O:: type 7 oxo, two lone pairs on O. 111 M - O- type 42 M <-:O< type 6 ether and pair. M - O:=C type 7 two lone pairs on O-, coordinately sat'd metal. coordination between 44 and lone pair on type 6, can dock with alcohol oxygen; alternatively, specify three bonds and lone one lone pair on O, MMX recognizes this and oxo + M = O- type 46 one lone pair on O+, coordinately unsat'd metal. to HALOGENM - F, M - Cl, M - Br, M - I, can be terminal or bridging, specify each bond. to HYDROGENM - H type 5 M - H* - M type 45 to CARBON/ M - C- type 1 \ terminal hydride. bridging hydride. sigma alkyl, specify 0144 bond. M - C= type 2 sigma vinyl, specify 0244 bond. M - C<| type 22 sigma cyclopropyl, specify 2244 bond. M - C=O type 3 sigma acyl & bridging carbonyl, specify 0344 bond. M - CO+ type 4 terminal carbonyl or terminal cyano, specify 0444 bond; Note that terminal carbonyl has a triple bond between C & O so that the O is PCMODEL will recognize this if a neutral O is used. a really O+ M - C+< type 30 metal carbene, specify 3044 bond. M - C:< type 48 specify 4448 bond, possible bridging with lone pair. / M <-:C- type 48 \ coordination only. 112 to SULFURM -:S:- R type 15 two lone pairs on S, coordinately sat'd metal. M = S:: type 38 two lone pairs on S. M <-:S:< type 15 coordination between 44 and lone pair on type 15, can dock for thioether and thiol sulfur or specify three bonds to S- one lone pair. M = S:+- type 16 one lone pair on S+, coordinately unsaturatedd metal. to PHOSPHOROUS/ M <-:P- type 25 \ coordination to lone pair or specify all four bonds (no lp). to METALSM - M 4444 bond MMX will alter natural bond distances if bond order is specified. COORDINATION is possible with the following ligands: ::O< type 6 ::O= type 7 / :N- type 8 \ :N type 10 ::S< type 15 / :P- type 25 \ / :C- type 48. \ Pi coordination also from types 2, 4, 29, 30, 40, and 48 carbons. 113 Chapter 16 File Formats 16.1 PCM File Format The PCM file format is a free format, context driven grammar for the description of molecular structures. This gives the user more and easier control of their structure files for additions and corrections, and leaves room for expansion of the definition of the force field. The context also allows for greater error correction within the program. At the end of this section is an example of a PCM file which describes the structure in Figure 6.1. Key words have been printed in bold for clarity. In this structure, we have included substructures, Pi atoms, hydrogen bonding, a metal, atomic charge, and coordinate bonds. The features of the file are fairly straight forward. From the top is the file type marker {PCM which indicates that the file is a PCM type file. This is required of all PCM files so that PCMODEL and MMX will recognize them. Immediately following the file type marker, on the same line, is the name of the structure. This name may be up to 58 characters long. On the next line appears NA followed by a number. This tells the number of atoms in the structure. This number is optional and is used only to check for consistency. Next, is SS 1 which introduces substructure number 1 and gives it a name which follows. The name can be up to 20 characters long. This is also optional. Currently, this statement only gives the substructure a name though at some point, it may be used to tell other aspects of the substructure. The fourth line contains FLags: EINT UV. Currently, the following flags are defined: EINT 0: dipole interaction energy will be calculated excluding interactions between dipoles with a common carbon. 1: as above but with all interactions. 2: dipole interaction calculation suppressed. 3: charge interaction energy will be calculated (excluding interactions between atoms bound to a common atom). If this option is used you must read in atomic charges. 4: charge interaction energy used. Charges calculated from bond dipoles with additions for pi atom charges. UV 0: if pi calculation, will be prompted before minimization: Number of electrons? Singlet, doublet, triplet, ? RHF or UHF calculation ? if singlet, RHF then restrictions on wave function? # of identical pairs of atoms? atom numbers of pairs? # of sets of identical bonds? atom numbers of bonds of bond pairs ? 1: default to singlet RHF pi calculation - no questions. 114 2: default doublet UHF pi calculation (for mono radicals) no questions. DIELC values give a dipole-dipole Floating point value of the new dielectric constant. Negative distance dependent dielectric constant. (nonsense with interactions). Line 5 contains the first atom record. After the atom specifier AT, the index number appears. These are the atom number and are used to reference the bond numbers. Next after some separator, usually a comma though a colon or a space will do, is that atom type number (see chapter 7 for a description of atom types). In the case of metals, the metal symbol is included in this space instead of the atom type number as in the sixth atom record. Next, appears some separator; we use a colon here for clarity. Then in order, is X, Y, and Z in angstroms. After the next separator, the bond marker, B, appears the list of bonds attached to the atom. 2,1 means a bond to atom two is a single bond. In atom 6, you will notice 10,9, which indicates a metal coordinate bond (type 9) to atom 10. At the end of the first few lines is a C followed by a number. C specifies a charge. Again looking at atom 6, an M appears. Following M is the specified electronic state of the metal, in this case 3 for low spin. R introduces the covalent radius. This number is used to determine the bond lengths of all ligand attachments to that metal. The record for atom 8 contains an H which indicates that it is a hydrogen bonding hydrogen. Atom 9 contains a P which marks it as a pi atom and an S, which refers to the list of substructures of which this atom is a member. The comma after the S is optional but is added for clarity. Finally, the structure file is closed with a }. This is mandatory so PCMODEL will know when to stop reading. 115 Figure 6.1 Structure of molecule described in PCM file below. 116 PCM Example File {PCM example pcm file NA 31 SS 1cyclo pentadiene FL EINT4 UV1 PIPL1 AT 1,8:5.00395,5.41685,4.14865 B 2,1 5,1 8,1 14,1 C .04109 AT 2,1:5.35786,3.99136,4.43375 B 1,1 3,1 15,1 16,1 C .04758 AT 3,3:3.89305,3.05742,4.72868 B 2,1 4,2 7,1 C .31634 AT 4,7:2.81165,3.08691,5.38735 B 3,2 6,9 17,1 18,1 C-.29483 AT 5,1:4.01102,5.78059,5.13175 B 1,1 6,1 19,1 20,1 C .00583 AT 6,Fe:3.37201,4.37477,5.09242 B 5,1 4,9 9,9 10,9 11,9 12,9 13,9 M3 R1.26000 C1.00000 AT 7,1:4.34527,1.64177,4.88598 B 3,1 21,1 22,1 23,1 C .04175 AT 8,23:5.80025,6.06569,4.07001 B 1,1 H C .15724 AT 9,48:2.72317,5.71177,3.69643 B 10,1 13,1 6,9 24,1 S, 1 P C-.03818 AT 10,2:2.74283,5.08259,2.49706 B 9,1 11,2 6,9 25,1 S, 1 P C-.03815 AT 11,2:2.37909,3.77508,2.58554 B 10,2 12,1 6,9 26,1 S, 1 P C-.03815 AT 12,2:2.02517,3.57846,4.02085 B 11,1 13,2 6,9 27,1 S, 1 P C-.03815 AT 13,2:2.22179,4.80733,4.59105 B 12,2 9,1 6,9 28,1 S, 1 P C-.03815 AT 14,20:4.70902,5.38735,3.60795 B 1,1 C-.21000 AT 15,5:5.98704,3.92254,5.39718 B 2,1 AT 16,5:5.92805,3.54897,3.55880 B 2,1 AT 17,20:2.37909,2.71334,4.92530 B 4,1 C-.05250 AT 18,20:2.75266,2.61503,5.84941 B 4,1 C-.05250 AT 19,5:3.46049,6.68504,4.76800 B 5,1 AT 20,5:4.51240,6.04603,6.10501 B 5,1 AT 21,5:3.51947,.88478,4.78767 B 7,1 AT 22,5:5.12192,1.35667,4.14865 B 7,1 AT 23,5:4.80733,1.51396,5.89856 B 7,1 AT 24,5:2.94928,6.78335,3.89305 B 9,1 S, 1 C .03818 AT 25,5:3.04759,5.59380,1.55329 B 10,1 S, 1 C .03815 AT 26,5:2.31027,3.01810,1.76957 B 11,1 S, 1 C .03815 AT 27,5:1.67126,2.64452,4.53206 B 12,1 S, 1 C .03815 AT 28,5:2.02517,5.05310,5.65279 B 13,1 S, 1 C .03815 AT 29,21:6.64571,6.42943,4.91547 B 30,1 AT 30,6:6.48842,6.06569,4.91547 B 29,1 31,1 AT 31,21:6.90132,5.87890,4.91547 B 30,1 } The PCM file syntax or grammer is given below. PCMFILE --> ( {PCM [NAME(60)] (ENTRY) * 117 }) ENTRY FIX_REC} --> { SSNAME | ATOM_REC | NATOM | FLAGS | CONST | SSNAME --> SS [SP] NUM(16) [SP] [NAME(20)] NATOM --> NA NUM() FLAGS --> FL [SP] ({ PR | UV | EINT | PIPL } [NUM()] SP) * CONST --> CO { ATOM_REC --> AT [SP] NUM() [SP] ATYPE SP X,Y,Z ([SP] ATFIELD)* FIX_REC --> FIX { ATOM NUM() ( X Y Z ) | DIS NUM() NUM() ( R FLOAT K FLOAT) } ATYPE --> { NUM(79) | NAME(2) } X,Y,Z --> FLOAT SP FLOAT SP FLOAT ATFIELD --> { BONDS | SUBSTR | ATOMFLG } BONDS --> B [SP] NUMBND SP (SP ATNUM,BNDORD )NUMBND NUMBND --> NUM(10) ATNUM,BNDORD --> NUM() (SP) NUM(10) SUBSTR --> S (NUM(16) SP)* ATOMFLG --> FL { P | M NUM(3) | H | C FLOAT | R FLOAT } * NAME(n) --> letter{letter|digit|punc}* for size <= n NUM(n) --> {digit} for value <= n SP --> {comma|blank|colon|tab} FLOAT --> [-](digit)*[.](digit)(digit)*[{e|E}[{-|+}(digit)(digit)*] letter digit --> character a-z A-Z $ _ --> character 0-9 { } - choose exactly one: all choices separated by | ( ) - grouping: multiple tokens treated as one token * - zero or more occurrences of previous token [ ] - optional (one or zero occurences) BOLD characters appear exactly Starter token MUST appear in column one ALL OPTIONAL SP NOTE: If the removal of an SP(space) from a string would place two members of the same token primitive class adjacent, the SP is not optional! 118 16.2 MMX Input Files It is a pleasure to acknowledge the contributions of Professor Allinger and his students to the algorithms and constants used in MMX whose progenitors are MM2 and the pi routines from MMP1. PCMODEL can read: A) a single structure file or B) a file containing multiple but separate structure files. For option B the first three characters on the first line of each new structure must be MMX. This tag is used by PCMODEL to recognize the start of a new structure. Each structure contains complete information about that structure. The file format for an MMX and MM2 file are similar, differing only in the lack of a line of logical variables to mark pi atoms in the MM2 file format. The file formats which follow are for FORTRAN formatted files, that is column placement is critical if the file is to be interpreted correctly. The format descriptors used in fortran are: a# character string of # length i# integer value up to # digits in size f fixed floating point number Thus the format for line one (see below) says to read 30 fields of two character (30a2), a series of integers that are 5 digits, 2, 3, 3, and 3 digits in length (i5,i2,i3,i3,i3) and a floating point number that is 5 units wide with no number beyond the decimal point (ie 10. ). For a more complete description please see any Fortran programming guide. The most important idea to remember is that data must be in specific columns in a fortran formatted file. First line: columns 1-60 format (30a2, i5,i2,i3,i2,i3,f5.0) 61-65 N number of atoms including lone pairs. 67 IPRINT print control ID name, title, or information Initial Calculation Only: 0: 1: 2: 3: 4: 5: Part 1-Minimize minimum minimum full simple minimum no print 0 or 1 simple; 2 or 3 full printout. Part 3-Final full (can be 100+kb) simple (useful)* full (can be 100+kb) simple minmum (bare bones) (Driver has its own out files) 119 * simple print omits VDW interactions <.1 kcal/mol 70 72 NRSTR INIT 0: 0: 74 IDOCK docking — if zero then none — but MMX can provide other options including simulated annealing of intermolecular interactions. These require the beginning atom number for the substructure in the atom list. This number is on NCON line (3rd line). 75 NCONST 0: no restricted atom data standard minimization no added constants 1: 1: 1: yes (see below) initial calculation only added constants If NCONST = 1, added constants may be appended to input file — see below — or in the form of a file which will be read if there are no input lines after the 13th line as defined below. WARNING, if there are added constants, the use of the multi coordinate input files will require that the added constants be in the input file NOT in an external file.Since PCMODEL now uses a text file of added constants this part of the MMX file format is not used. 76-80 time - ignored in all versions Second line 1-60 format(60l1,i2,2x,i2,2x,2i2,4i1,2i2) LOGARY: t or f in each column indicates whether or not the atom number represented by the column number is to be considered a pi atom in a VESCF calculation. If no atom numbers are marked t, no pi calculation will be performed. If there are more than 60 atoms, add more lines with these logical variables up to 4 lines total. 62 NPLANE 0: planar pi calculation 1: non planar In a planar pi calculation, the first calculation is on a Huckel matrix whose elements depend on the atom types and geometry Diagonalization gives a density matrix which is used along with Slater orbital exponents and calculated overlap integrals to give the elements of the FOCK matrix which is diagonalized to give a new density matrix. Subsequent iterations give a self-consistent field with an invariant energy. In a non planar calculation two scf calculations are required-one on the non planar system and one on a planar projection. The bond orders of the planar projection are used to weight the natural distances, force constants, and two-fold torsional barrier terms, see below (ADDED CONSTANTS). 66 JPRINT: print out for pi calculation 1st SCF during minimization 120 0: 1: 2: 3: energy only energy + matrices energy + matrices ditto energy only energy only energy + matrices on each iteration energy + matrices on each iteration 69-70 LIMIT limit for self-consistency (10)-this integer (in ev). default is (10)-5 72 ITER maximum number of SCF iterations to be run. (ignored in this version with open shell pi calculation) 73 IHBD 0: 1: no read of hydrogen bonding logical array-all OH, NH, & SH hydrogens participate in hydrogen bonding. read hydrogen bond logical array after line 7 below; first line for 80 atoms; additional lines for up to total atoms; array marks which hydrogen atoms will hydrogen bond. 74 ICOV 0: 1: no metal atoms are present in input file read line containing metal type and radius (3 different metals maximum) then read logical array of atoms coordinated to each metal; lines must be after the hydrogen bond array or after line 7. 75 IUV 0: 1: 2: if pi calculation, MMX will ask for options before minimization: number of electrons? singlet, doublet, triplet, etc.? RHF or UHF calculation? if singlet, RHF then restrictions on wave function? # of identical pairs of atoms? atom numbers of pairs? # of sets of identical bonds? # of identical bonds and # of atom pairs? default to singlet RHF pi calculation - no questions. default doublet UHF pi calculation (for mono radicals) no questions. 76 IHUCK 0: 1: for full VESCF calculation before first MM energy minimization for Huckel calculation (of planar systems) before first MM; subsequent minimizations will be full SCF 78 NSETAT - number of sets of equivalent pi atoms 121 80 NSETBD - number of sets of equivalent pi bonds The previous two options are over-ridden by IUV greater then zero. Then lines of logary (in 80l) for atoms beyond 60. if NSETAT .gt. 0, must read ISETA(I) in 10i4, number of equivalent atoms in each set; then must read nsetat lines in (20i4) which contain the atom numbers in each set. if NSETBD .gt. 0, must read ISETB(I) in 10i4, number of equivalent bonds in each set; then must read lines in (20i4) which contain the atom numbers, in pairs, for each bond. A new set must start a new line. Third line format(i5,1x,i1,2x,f5.1,5x,9i5,5X,2i5) (if no pi atoms in molecule with more than 60 atoms — otherwise this is the 4th line) 1-5 NCON # of connected atom lists (not atoms) to read in 30 Max. 7 IDYN 0: 1: no dynamics dynamics program is run interactively — After filename is given, user will be asked: Timestep in femtoseconds (1.0 fsec is default) Viscosity in cp (0.000 is default) Temperature of Bath (300.K is default, initial sample temperature is 300.K so implies no heat in or out) Time constant for heat transfer (1015 femtosecond is default, this implies no coupling of bath to sample). After 20 cycles, user can alter values and number of cycles. Dynamics can be used to remove KE increasing the viscosity or cooling with a time constant ~ timestep so that an unstable structure can be optimized — slowly — invariably to a local minimimum. At a given temperature kinetic and potential energy are conserved an provide ranges of motion. A minimized structure can be heated to escape a local minimum then cooled perhaps to a global minimum. Global optimization can also be performed by minimizing many initial structures generated by MODEL in MULTIC mode or PCMODEL in MULTOR mode - see NDRIVE 11-15 DIELE dielectric constant. If 0., default to 1.5. 122 If negative, a distance dependent dielectric constant is used in the chargecharge interactions (DIELC=Rij). If a negative dielectric is used with the dipoledipole calculations, nonsense will result. 16-20 JSTART atom number begining substructure in atom list-for docking onlyIDOCK of first line (col 74) must be set to >0. 25 IBUT 0: no 1: yes cyclopropropanes or cyclobutanes present 26-30 NATTCH # atoms attached to previously defined atoms. 31-35 NSYMM number of symmetry matrices to read in. PCMODEL writes 0 for this variable. 36-40 NX number of coordinate replacement lines to read — this option is unnecessary with structure file generation programs like MODEL, and PCMODEL. See QCPE 395 documentation for its use. The coordinate replacement lines must immediately follow the cartesian coordinate input. 45-50 LABEL 0: names and weights of atoms defined in program are used. #: number of different atom types whose names and weights will be changed below. PCMODEL writes 0 for this variable. 55 NDC 0: dipole interaction enery will be calculated excluding interactions between dipoles with a common carbon. 1: as above but with all interactions. 2: dipole interaction calculation supressed. 3: charge interaction energy will be calculated (excluding interactions between atoms bound to a common atom). If this option is used you must read in atomic charges below. 4: charge interaction energy used. Charges calculated from bond dipoles with additions for pi atom charges. PCMODEL writes 0 or 4 (default). 60 NCALC determines crystal conversion and/or orientations to be performed on input coordinates. 0: 1: 2: no crystal options. input coordinates are reduced crystal coordinates. They will be converted to cartesian coordinates (see below). input coordinates will be oriented according to instructions below. 123 3: Combination of 1 and 2 above. PCMODEL writes 0 for this variable. 65 HFORM 0: no 1: yes heat of formation calculated 2: read new values for partition function contribution formation. PCMODEL writes 1 for this variable. to the heat of 80 NDRIVE 0: no 1: endocyclic dihd. driver -1: side chain dihd.driver For options -1 and 1, a data line must be added before an added constants list at the end of the input file. See below. In MMX (a separate batch processing program) if NDRIVE >= 10000: sets of coordinates can be read in after all other input. Each set must consist of one line in format i5 which indicates the number of the set (starting from 1), and the coordinates must be in the standard format (see SIXTH LINE below). The previously read connectivity information will be used in the calculation. Files with the filename + sequentially numbered extension will be generated. A brief output file, *.SUM, with the filenames and energies will also be generated; an energy ordered file MMXE.ORD is also generated. In MMX: if NDRIVE=-9999: global minimum finder by simulated annealing. Requires additional input lines after the loghbd and logmet lines of logicals. OPTIONS FROM LINE ABOVE: If LABEL _ 0 add # of LABEL lines in format (i5,3x,a2,f10.5) 4-5 ITY(i) atom type whose name and weight are to be redefined. 9-10 NAM(i) two character name for new atom type. 11-20 WGHT(i) Atomic weight for the atom. If NDC = 3 add lines whose format is 8f10.5 listing the charge on each atom-for N total atoms including lone pairs. Fourth line(s) NCON lines each in format (16i5) 124 ICONN(i,j) i=number of the line (1 to NCON), j=number of entry on line (from 2 to 16) Each list contains up to 16 CONTIGUOUS atoms and each list can repeat atoms in a previous list. Cyclohexane would have one list with values 1,2,3,4,5,6,1 Bicyclo[3.2.1]octane would have two lists — the cyclohexane list above and a second list with values 1,7,8,3 There are no restrictions on lists other than to avoid non contigous atoms during the sequence. Fifth line(s) NATTCH lines each in format (16i5) number of lines sufficient to add all atom pairs up to NATTCH in format (16i5). The pairs are: JATTCH(i), KATTCH(i) where i equals 1 to NATTCH. JATTCH(i) is an atom already defined either in NCON or previously defined as a KATTCH atom. KATTCH(i) is an atom attached to JATTCH(i). For cyclohexane NATTCH = 12 which would require two lines. The values are: 1,7,1,8,2,9,2,10,3,11,3,12,4,13,4,14 5,15,5,16,6,17,6,18 Sixth line(s) COORDINATES format(2(3f10.5,2i5)) 1-10 X(1) Coordinates in Angstroms of atom 1-These may be reduced crystal coordinates if NCALC =1 or 3. 11-20 21-30 31-35 36-40 Y(1) Z(1) ITYPE(1) MMX atom type( see Table of Atom types) MATOM(1) 36-38 atom number this atom is multiply bonded to. 39 (for metal atoms only 0:coordinately saturated; 1:unsaturated 2:>18 electrons 3:square planar). 40 Number of bonds to atom defined in 36-38 minus 1; singly bonded to others will have matom = 00000 41-50 X(2) 125 Non metal atoms 51-60 61-70 71-75 76-80 Y(2) Z(2) ITYPE(2) MATOM(2) Repeat lines until all coordinates are included. Seventh line(s) NX > 0 COORDINATE REPLACEMENT or ATOM ADDITION See documentation to QCPE 395 or QCPE MMP2(85) for options and data structure. Seventh line(s) If NCALC = 1 or 3 CRYSTAL CONVERSION in format (6f10.5) If reduced crystal coordinates were read in above instead of cartesians coordinated, the following parameters will convert them to cartesian. 1-10 11-20 21-30 31-40 41-50 51-60 A Dimensions of unit cell in Angstroms (a,b,c) B C ALPHA Angles associated with unit cell. BETA GAMMA Eighth line(s) Hydrogen Bonding flags If IHBD=1 format(80l1). If N >80, more lines in format (80l1) are read. These should be "f"s unless a particular hydrogen, whose atom number is represented by the column number, will participate in hydrogen bonding-then a "t" should be in the column. Ninth line(s) If ICOV=1, Metal Names, Covalent Radii and Charge Program checks number of metal atoms present (itypes 44,56,57) and reads line of metal characters, covalent radii, and the charge on each metal (necessary for isolated ions & might be useful for organometallics if electrostatics are used) in format (3(a2,f8.6),9f5.2); these variables are amet,rcova,bmet,rcovb,cmet,rcovc, and chrgmet(i), i=1,9. [Changing rcova will change the covalent radius used for all bonds involving the metal amet.] Then the number of metal logical lines of format(80l1) are read. A t or f indicates whether or not the atom number represented by the column number is coordinated (not bound as would appear in the NCON or NATTCH lists) to the first (or second etc. 9 Max) metal atom in the atom number list. If more than 80 atoms are present more lines should follow - in (80l1) format-to mark the rest of the atoms. 126 Tenth line(s) If NSYMM .ne. 0 read NSYMM lines in format(2i4,9f8.5) 3-4 Is number of the independent atom in the symmetry-related pair — it will be moved during the minimization. 5-8 Ks number of the dependent atom in the pair. Its coordinates are calculated from a symmetry matrix operating on IS. ELEMENTS OF SYMMETRY MATRIX - ON SAME LINE 9-16 17-24 25-32 33-40 41-48 49-56 57-64 65-72 73-80 SXX Amount by which X(K) must be changed when X(I) is moved by 1 Å in order to maintain molecular symmetry. SXY Change in Y(K) for X(I) change =1. SXZ Change in Z(K) for X(I) change =1. SYX Change in X(K) for Y(I) change =1. SYY Change in Y(K) for Y(I) change =1. SYZ Change in Z(K) for Y(I) change =1. SZX Change in X(K) for Z(I) change =1. SZY Change in Y(I) for Z(I) change =1. SZZ Change in Z(K) for Z(I) change =1. An atom may be used as Is as often as necessary but cannot appear in another symmetry pair as Ks. In order to specify symmetry correctly, the coordinate axes used in the minimization must be known. Do an initial calculation with INIT=1. This procedure is retained from MM2 but has not been tested in MMX. Eleventh line(s) Restricted atoms If NRSTR =1 first line in format (i5) is number of atoms whose motions are restricted, the remaining lines in format (16(i2,3i1) define the restrictions in any or all of the X,Y, and/or Z directions. Thus the atom may be kept along an axis, or in a plane, or at a point. 1-2 AT Number of the atom whose motion is to be restricted. 3 4 5 X Y Z 0: 0: 0: no restriction 1: no X axis movement. ditto 1: no Y axis movement. ditto 1: no Z axis movement. repeat up to 16 times per line. Note that this will fail if the atom number to restrict is greater than 99. 127 This option is often considered for transition states, but its use is limited in that connection. It is better to use transition state atoms whose constants can be generated by PCMODEL. Twelfth line if HFORM =2 read a line in format (3f5.2,f10.3) 1-5 POPI population increment (Enthalpy contribution due to higher energy conformations) Default=0 6-10 TORI torsional increment (Enthalpy contribution due to torsional degrees of freedom) Default=0 11-15 TROTItranslation-rotation increment (Enthalpy increment due to translational and rotational degrees of freedom) Default=2.4 kcal/mol. 21-30 Experimental heat of formation (kcal/mole) 31-40 Experimental error (absolute value) 41-80 Literature reference (optional) Thirteenth line Dihedral Driver Information if NDRIVE is not equal to 0. if NDRIVE < 10000 and NDRIVE .ne. -9999 in format(2(4i5,5x,3f5.0)) (Note that this line usually occurs at the end of an MM2 input file, but in MMX it must preceed an added constants list which is appended to the input file.) This is used to drive one or two dihedral angle(s) through a range of values and to minimize all other degrees of freedom at each point. 1-5 6-10 11-15 16-20 26-30 31-35 36-40 41-45 46-50 51-55 56-60 66-70 71-75 76-80 M1 M2 M3 M4 atom numbers for first dihedral angle. START1 starting angle FIN1 final angle DIFF1 step or increment N1 N2 N3 N4 atom number for second dihedral angle. START2 starting angle FIN2 final angle DIFF2 step or increment 128 Before use, remove restricted motions from atoms to be moved and symmetry. NDRIVE may be -1 for side chain or 1 for angles whose 2nd & 3rd atoms are confined to rings. The side chain driver is useful if the dihedral is not part of a ring. It carries out a rigid rotation for each step in dihedral angle. The endocyclic drive is confined within 0 and 180 degrees or 0 and -180. The step cannot be large (5-10 degrees is normal). The minimization will stop if either 0 or 180 degrees is achieved. Use the side chain driver if possible. IF NDRIVE >= 10000 - see description for Third line above-requires multiple sets of cartesians. MMX option only IF NDRIVE = -9999 - Global minimization by simulated annealing. MMX option only 1st line: format 6i5 krbnds kring -0: number of dihedrals to rotate, 30 MAX no ring 1: ring irange for rings-angle window for closure usually 20 degrees krand 0: randomize all dihedrals before an energy check (usual) #: randomize # dihedrals in the sequence below before an energy check igen - generating function type (use 0) 0: 15*temperature*(tan(pi*(ran-.5)) 0. 0 TORSION CONSTANTS - NT lines in format (4i5,3f10) from: 1 over 2 V sub 1 left ( 1 + cos OMEGA right ) + 1 over 2 V sub 2 left ( 1 - cos (2 OMEGA) right ) + 1 over 2 V sub 3 left ( 1 + cos ( 3 OMEGA ) right ) 1 2-5 6-10 11-15 16-20 21-30 JBT I1 I2 I3 I4 V1 31-40 V2 41-50 V3 4 for cyclobutane torsion 0 for all others atom type numbers for dihedral; I2>I3 or if I2=I3, I10, 0 deg is potential energy maximum, 180 deg is potential energy minimum. Two-fold barrier; if >0, 90 deg is potential energy maximum 0 and 180 deg are energy minima. Three-fold barrier; if >0, 0 and 120 deg are energy maxima 60 and 180 deg are energy minima. Note that ethylene has four torsional interactions making up the ca 60 kcal barrier so V2=15 for type 2 - type 2 torsions. Ethane has six torsional interactions, etc. 131 next line if NS > 0 STRETCHING CONSTANTS — NS lines in format (2i5,6f10.5) from: EC = 143.88*1/2ks*(1+CST*(r-r0))*(r-r0)2 E sub c = 143.88 * 1 over 2 k sub s left ( 1 + cst ( r - r sub 0 ) right ) cdot ( r - r sub 0 ) sup 2 where CST is cubic stretch term. 1-5 6-10 11-20 21-30 31-40 I atom type number K atom type number; I .le. K S stretching constant (ks above) in md/angstrom for bond I-K T1 natural, minmum energy bond length (r0 above) in angstroms T2 if I and K have one or less hydrogens attached T2 is the length used; if T2 is zero T1 is used. 41-50 BMOM bond moment for pair I,K; if >0, K is more electronegative atom 51-60 SLPS for pi atom pairs: S = S-SLPS + SLPS * rhoI,K 61-70 SLPT for pi atom pairs: T1 = T1+SLPT - SLPT * rhoI,K Note that the dipole-dipole interaction potential energy is: Emu= 14.39418*BMOM(I,K)*BMOM(M,N)*(cos X - 3* cos A * cos B)/ DLC*r3 where r is the distance between the midpoint of the two bonds I-K and M-N; X is the angle between the two bonds; A is the angle between bond I-K and line represented by r; B is the angle between bond M-N and line represented by r; DLC is the dielectric constant whose default is 1.5. The dipole moment is calculated from the vector sum of all bond moments. If a pi calculation is performed, the dipole moment from the pi system is added vectorially to the sigma dipole moment. There is presently no calculated interaction between the pi and sigma dipoles. next line if MUA > 0 BOND DIPOLE CONSTANTS BY ATOM TYPE MUA lines in format (2i5,f10.5) 4-5 I 6-10 k 11-20 BMOM atom type number atom type number; I _ K bond moment for pair I,K; if >0, K is more electronegative atom It is more consistent to change the BMOM in the added Stretch constants since all six values are read from the data base. next line if MUB > 0 BOND DIPOLE CONSTANTS BY ATOM NUMBER 132 MUB lines in format (2i5,f10.5) 4-5 N1 9-10 N2 11-20 V12 atom number of the less electronegative atom atom number of the more electronegative atom new bond moment for bond N1-N2. V12 should be negative if N1 is more electronegative than N2. (untested in MMX) next line if NV > 0 VAN DER WAALS' CONSTANTS NV lines in format (i10,2f10.5) EV = eps*290000*e-12.5/p - 2.25*p6 where p = (RDi+RDk)/r0 < 3.311 eps = sqrt(EPi*EPk) "hardness" r0 effective distance (for CH bonds the H is effectively 10% closer to the C than the actual C-H distance). EV = eps*336.176*p2 if p > 3.311 9-10 IT atom type number whose parameters are to be changed 11-20 EP epsilon (kcal/mole) for type IT atom 21-30 RD radius in angstroms for type IT atom The user has no control over the parameters used for hydrogen bonding and coordination to a metal. These are included in the vdw parameters because the vdw attractive term for hydrogen bonding and for the lone pair or pi atom interaction with a metal is proportional to p2 not p6. The attractive are much larger than 2.25, depend on the donor and acceptor and angles, and is matched by a larger repulsive term. next line if NB > 0 BENDING CONSTANTS NB lines in format (i1,i4,2i5,2f10.5,i5) from: EB = 0.043828*1/2*kb*((theta0-theta)2)*(1+SF*(theta0-theta)4) 1 2-5 where SF is sextic bending constant (.00700E-5). JBN 3 for cyclopropane angle 4 for cyclobutane angle I1 atom type number; I1 0 STRETCH-BEND CONSTANTS NSB lines in format (4f10.5) from: ESB = 2.51118 * ksb * theta * (r1,2 + r2,3) where ksb are constants described below; theta is angle 1-2-3; r1,2 is distance between atoms 1 and 2; r2,3 is distance between atoms 2 and 3. 1-10 SB1 constant for angle a-f-c where f is a 1st row atom; a and c are any non-hydrogen atoms. Both bonds are considered in ESB. Default value is 0.12. 11-20 SB2 constant for angle a-s-b where s is a 2nd row atom; a and c are any non-hydrogen atomsDefault value is 0.25. 21-30 SB1H constant for angle a-f-H where f is a 1st row atom; a is any non-hydrogen atom; only bond a-f is considered in ESB. Default value is 0.09. 31-40 SB2H constant for angle a-s-H where s is a 2nd rwo atom; a is any non-hydrogen atom; only bond a-s is considered in ESB Default value is -0.40 next line if NH > 0 HEAT OF FORMATION BOND AND STRUCTURAL PARAMETERS NH lines of format (2i5,2f10.5,i5,5x,5a4) 1-5 6-10 11-20 21-30 IT KT BE SBE atom type number defining a bond or structural feature number atom type number defining a bond (zero if structural feature) bond enthalpy increment for IT-KT bond or structural feature bond entropy increment for IT-KT bond (zero if structural) 134 35 NEW 0: Default comment on bond enthalpy (use zero if structural) 1: change or add comment on bond enthalpy 41-60 NTITLE Comment on bond enthalpy (ignore if structural) 16.3 Mopac and Ampac Files Mopac input and output files are 'free format' internal coordinate or cartesian files. The free format refers to the fact that data may be entered at any position on a line, there is no fixed column number in which the data must appear to be read correctly. The internal coordinate format consists of lists of bond lengths, angles and dihedrals and the defining atoms which describe the molecular geometry, as opposed to a list of cartesian coordinates for all the atoms. In internal format for any atom (i) there is an interatomic distance in Angstroms from an already defined atom (j), and interatomic angle in degrees between atoms i and j and a previously defined atom (k), where j and k are different, and a dihedral angle in degrees between atoms j,k and a previously defined atom (l), where l is different from j and k. Atom 1 has no coordinates since this is defined as the origin, atom 2 is connected to atom 1 by an interatomic distance only, and atom 3 is connected to atom 1 or atom 2 by an interatomic distance and makes an angle (either 3-1-2 or 3-2-1) with no dihedral angle defined. A mopac file for benzene is given below : am1 C C C C C C H H H H H H 0.000000 1.400211 1.399883 1.400132 1.399876 1.400199 1.103109 1.103110 1.103109 1.103109 1.103109 1.103109 0 1 1 1 1 1 1 1 1 1 1 1 0.000000 0.000000 119.996750 120.005653 119.993233 120.006828 119.998314 120.002739 119.998428 120.002640 119.997231 120.001671 0 0.000000 0 0 0 0 0 0.000000 0 1 0 0 1 0.000000 0 2 1 0 1 0.000000 1 3 2 1 1 0.000000 1 4 3 2 1 0.000000 1 5 4 3 1 180.000000 1 1 2 3 1 180.000000 1 2 3 1 1 0.000000 1 3 2 2 1 0.000000 1 4 3 3 1 0.000000 1 5 4 4 1 0.000000 1 6 5 5 line 1: keywords separated by one or more spaces such as : am1 line 2: title line up to 60 characters long: blank line 3: second title or comment line up to sixty atoms long: blank line 4 to end : Atom Symbol Dist Opt Angle Opt Dihed Opt NA NB 135 NC The atom symbol is the atomic symbol for that atom. The distance is the interatomic distance between the current atom and the atom number given in the NA column. Thus atom 2 is referenced to atom 1, atom 7 (which is a hydrogen) is reference to atom 1 also. The Opt columns determine whether this parameter (distance, angle or dihedral) will be optimized by Mopac, with a 1 to optimize and a 0 to not optimize. The angle is the angle formed by the current atom and the atoms NA and NB. Thus atom 4 is referenced to atom 3 for the distance and makes the angle of 120.005 with atoms 3 and 2 ( angle 4-3-2). The dihedral angle is defined for atoms 4-3-2-1 to be 0.0 degrees. For a more complete description of Mopac files and options please see the MOPAC documentation which is available from QCPE or from Serena Software. 16.4 X-RAY Files Since there is no universally accepted file format for x-ray data, we have written a free format file parser that should allow you to input the data in any format. Our routines expect: Line 1: Title character string of up to 80 characters Line 2: Cell Parameters A,B,C,Alpha, Beta and Gamma Line 3 to end: X,Y,Z coordinates and atom symbol. Note that these routines do not read symmetry matrices or point groups. Thus we assume the coordinates are orthogonal and that the cell paramters are floating point numbers (including the decimal point). If you understand this then you probably have the necessary programs to output this type of data. A sample x-ray input file is included below. A set of dummy cell parameters to use with a set of Cartesian coordinates would be: 1. 1. 1. 90. 90. 90. (note you need the decimal point, all the cell parameters are read as real numbers). Test input file 1.0 1.0 1.0 90.0 90.0 90.0 0.124381 -0.144487 -0.435695 -1.526023 0.158658 0.185498 0.818900 1.213381 0.125534 0.638991 -1.256924 0.361156 -1.905993 1.082317 -0.230632 -2.152138 -0.671798 -0.115534 -1.491980 0.209408 1.267034 1.053019 1.088258 1.043743 s c o o h h h h 136 16.5 SDF and Mdl Mol Files 16.6 Chem3D and Tinker Files 16.7 Cambridge Structural Database Files 16.8 Alchemy and Sybyl Mol Files 16.9 Gaussian Input and Output Files 16.10 Gamess Input and Output Files 16.11 ADF, PQS, Hondo and Turbomole Files 16.12 Smiles Files 137 Chapter 17 Parameter Files All of the parameters, constants and atom type definitions for a given force field are defined in a text file. The format of this file is similar to that developed by Professor Jay Ponder of Washington University for the Tinker program. The files currently distributed with Pcmodel are: Mmxconst.prm Mm3.prm Mmff94.prm Amber.prm Oplsaa.prm Parameter file for MMX force field Parameter file for Allinger’s MM3 force field Parameter file for Halgren’s MMFF94 force field 17.1 Overview All the parameter files include a definition of the constants used for the various energy equations used by that force field, the atom types defined and the parameters required. The file is free format and data lines begin with a keyword that starts in column one followed by the data separated by one or more spaces. The information can be defined in any order since each line is parsed and interpreted. The beginning of the MMX force field parameter file is given below. MMX (1986) ############################## ## ## ## Force Field Definition ## ## ## ############################## forcefield MMX bondunit bond-cubic bond-quartic angleunit angle-sextic str-bndunit torsionunit vdwtype radiusrule radiustype radiussize epsilonrule atom-14-scale a-expterm b-expterm c-expterm chg-14-scale dielectric 71.94 -2.0 2.333333 !! (7/12) * bond-cubic^2 0.02191418 0.00000007 2.51118 0.5 BUCKINGHAM ARITHMETIC R-MIN RADIUS GEOMETRIC 1.0 290000.0 12.5 2.25 1.0 1.5 Definitions for some of the keywords are: Forcefield definition of the name of the forcefield 138 Bond_unit Bond_cubic Vdwtype Radiusrule Dielectric constant for converting bond constants to energy same as above or zero if cubic stretch not used Definition of vdw equation to use, Buckingham or Lennard-Jones combining rule for vdw radius default dielectric constant 17.2 Atom Types Atom type definitions begin with the keyword ‘atom’, followed by a numeric atom type, character atom type, a twenty character text description, atomic number, atomic weight, number of bonds, total bond order, and the atom class definition. In the example from MMX given below the first four atom types defined are all carbon, with atom type 1 being an sp3 carbon that forms four bonds, atom types 2 and 3 being sp2 carbons that form three bonds and finally atom type 4 which is a sp carbon and only forms two bonds. The information about bonds is necessary to automatically add hydrogen to an atom. The atom class definition allows the users to create many specific atom types without having to provide complete data for all of them. For example, MM3 defines the basic carbonyl oxygen as type 7 and then defines atom types 77 to 101 as specific types of carbonyls. In the data set there are specific stretching force constants for many of the carbonyl atom types, but if data is missing the default type 7 parameters are used. ## atom atom atom atom atom atom atom atom atom Atom Types 1 2 3 4 5 6 7 8 9 C C C C H O O N N CSP3 CSP2 ALKENE CSP2 CARBONYL CSP ACETYLENE HYDROGEN C-O-H, C-O-C =O CARBONYL NSP3 NSP2 6 6 6 6 1 8 8 7 7 12.011 12.011 12.011 12.011 1.008 15.999 15.999 14.007 14.007 4 3 3 2 1 2 1 3 3 4 4 4 4 1 2 2 3 3 1 2 3 4 5 6 7 8 9 17.3 Bonds The bond stretching function used in Pcmodel is a fourth order polynomial. Force fields such as Amber and Oplsaa are supported by setting the cubic stretch and quartic stretch terms to zero, while MM2, MM3, MMX and MMFF94 are supported by defining these terms. Es = bu*ks/2*(δr)2 *[1 – cs*( δr) + qs*(δr)2] Where: Bu Ks Dr Cs bondunit , conversion factor from md/A2 to kcal/mol-A2 stretching force constant actual bond length – defined bond length cubic stretching term defined in parameter file 139 Qs quartic stretching term defined in parameter file The keywords used for defining the bond parameters (force constant and defined bond length) are Bond, Bond3, Bond4, Bond5 and Bonddel. Parameter data begins with a keyword followed by the two atom types comprising the bond with the lower numbered atom type first. Next comes the stretching force constant and the defined bond length. The bonddel keyword only applies to MMFF94 and is used for bonds that are part of conjugated pi systems. Since MMFF94 does not support pi calculations it deals with delocalization by explicitly recognizing delocalized systems and using bond , angle and torsion parameters appropriate for this type of system. Thus the central bond of butadiene would be treated with a bonddel parameter for a type 2-type 2 bond. Examples of bond parameters are given below. bond bond3 bond4 bond5 bonddel 1 5 6 1 2 1 22 56 1 2 4.4900 5.130 5.7000 4.4900 5.3100 1.5247 1.0860 1.4250 1.5258 1.4300 17.4 Angles Pcmodel uses both in-plane and out-of-plane bending functions. The in-plane angle deformation function used is a sixth order polynomial in delta theta. Force fields such as Amber and Oplsaa use only the harmonic term while MMX, MM2, MM3 and MMFF94 use the higher order terms. Eb = au*kb/2*(δΘ)2*[1 + cf*( δΘ) + qf*( δΘ) 2 + pf*( δΘ)3 + sf*( δΘ)4] Where: conversion factor from md A/rad2 mol to kcal/deg2 mole bending force constant actual bond angle – defined bond angle cubic angle bending constant quartic angle bending constant pentic angle bending constant sextic angle bending constant Au Kb δΘ Cf Qf Pf Sf The keyword used for defining the in-plane angle parameters (bending force constant and defined angle) are angle, angle3, angle4, angle5 and angldel (MMFF94 only). Parameter data begins with a keyword followed by the three atom types of the atoms comprising the angle, the bending force constant and up to three defined angles. The first angle given is the default value and the value used if no hydrogens are attached to the central atom. If a second angle is present and not zero, it is used for angles with one hydrogen attached to the central atom. If a third angle term is present and not zero it is used for angles with two hydrogens attached to the central atom. Examples of angle parameters are given below. angle angle3 angle4 angle5 1 22 1 1 1 19 1 1 1 22 9 1 0.6700 0.1250 0.5500 0.6700 109.5000 50.2000 106.5000 109.5000 140 110.2000 0.0000 0.0000 109.9000 111.0000 0.0000 0.0000 111.0000 angdel 1 2 63 0.7680 127.9450 Pcmodel has two out-of-plane bending functions which are applied to sp2 atom types. The standard Allinger implementation uses the angles defined by the projection of the central atom onto the plane defined by the three attached atoms. MMFF94 uses the Wilson angles to define the out of plane deformation. The keyword is opbend and is followed by four atom types in the order of attached atom, central atom, attached atom, attached atom. The Allinger type implementations use only the second and third atom types (the first and fourth can be set to zero), while MMFF94 requires that all four atom types be defined. opbend opbend 0 1 2 2 1 1 0 2 0.1000 0.0300 (MMFF94) 17.5 Stretch-Bend The stretch-bend potential function is: Esb = ksb*(δΘ)*(δr) The keyword is strbnd and it is followed by the three atom types of the atoms defining the angle and three force constants. The force constants are ordered by the number of hydrogens attached to the central atom and the order is zero, one and two. strbnd strbnd 0 1 1 1 0 1 0.130 0.2060 0.080 0.2060 0.000 0.000 0 MM3 MMFF94 17.6 Torsions The torsion potential function is a six term fourier series in the cosine of the dihedral angle. Et = V1/2*(1+cosφ) + V2/2*(1-cos2φ) + V3/2*(1+cos3φ) + V4/2*(1-cos4φ) + V5/2*(1+cos5φ) + V6/2*(1-cos6φ) The Allinger based force fields, such as MM2, MMX and MM3, and MMFF94 use the first three terms of the series, while the harmonic force fields, such as Oplsaa and Amber, use only one of the first three terms. The keywords are torsion, torsion4, torsion5 and torsiondel, followed by the four atom types of the dihedral angle, the force constant and then the phase for that force constant. torsion torsion5 torsion4 torsiondel 1 1 3 2 1 1 1 5 1 1 1 1 1 1 9 2 2 141 0.185 +1 0.185 +1 0.000 +1 0.0000 +1 0.170 -2 0.170 -2 0.000 -2 0.0000 -2 0.520 +3 1.160 +3 0.250 +3 0.0550 +3 17.7 Van der Waals There are three different vdw functions programmed in Pcmodel. The Buckingham potential used by the Allinger force fields, the Leonard-Jones potential used by Amber and Oplsaa, and the buffered-7-14 potential used by MMFF94. Lennard-Jones Buckingham MMFF94 Evdw = 4E*(( A/r)12 -( B/r)6) Evdw = A' exp( -B ' /r) -( C/r ) 6 Evdw = 4E*(( A/(r+const))14 -( B/(r+const))7) The keywords are vdw, vdwpr and vdwmmff. The vdw keyword is used for basic vdw parameters and is followed by the atom type, the vdw radius and epsilon. The A, B and C constants are defined in the part of the parameter file dealing with general force field constants as are the combining rules. The MMX and MM3 force fields have separate entries for special pairs of atoms and this is done with the keyword vdwpr which is followed by two atom types the vdw radius and epsilon. This is primarily done for C-H interactions, but can also be used to describe other types of non-bonded interactions, such as that between metal ions and pi systems. The MMFF94 parameters are taken directly from Halgren’s published set of parameters and the vdw interactions are computed as given in “Merck Molecular Force Field.II. MMFF-94 van der Waals and Electrostatic Parameters for Intermolecular Interactions”, J Comp Chem, 17, 520-552 (1996). vdw vdwpr vdwmmff 1 1 1 2.040 3.560 1.0500 5 0.027 0.023 2.4900 3.8900 1.2820 - 17.8 Charge and Dipole Pcmodel implements a coulomb potential function, charge-dipole and dipoledipole potential functions. In the MMX force field charges are computed from the bond dipole moments. In MM3 the dipole moments are used directly in charge-dipole and dipole-dipole calculations. MMFF94 charges are computed as given in the J Comp Chem reference. In Amber the charges are entered directly in the parameter file and are taken from the Amber-95 JACS paper. For Oplsaa atom type charges are based on the chemical environment as encoded in a Smiles string, but if no charge is found in the parameter file MMFF94 charges are used. The keywords are dipole, charge, mmffcharge and bndchrg . dipole charge mmffchrg bndchrg 1 30 1 1 2 1 0.9000 1.000 0.0000 0.0000 0.0000 0.0000 E94 #C94 17.9 MM3 Specific angang strtors electroi 1 1 1 1 1001 3 0.240 0.059 -0.007 142 0.300 0.000 17.10 Pi Calculations MMX and MM3 use a PPP type scf calculation to modify the bond stretching and torsion parameters for pi systems. The pibond keyword is followed by two atom types, the bond stretching force constant, the bond length for a full pi bond, the bond moment (which is no longer used), the rate of change of the force constant with pi bond order and the rate of change of the bond length with pi bond order. The equations for modifying the pi bond length and force constant are: Force_constant = bkon - slpk + slpk*pbo; Bond_length = blen + slpl - slpl*pbo; Where : Pbo Bkon Slpk Blen Slpl piatom pibond pi bond order force constant from parameter file change in force constant with pi bond order bond length from parameter file change in bond length with pi bond order 2 2 1.0 2 -11.160 7.5000 11.134 3.25 1.3320 0.0000 143 3.25 0.841 5.486 2.8200 0.1700 -15.172 4