Molecular Modelling. Computational Chemistry Demystified. RSC Publishing. Interprobe Chemical Services, Lenzie, Kirkintilloch, Glasgow, UK

Transcription

1 Molecular Modelling Computational Chemistry Demystified Peter Bladon Interprobe Chemical Services, Lenzie, Kirkintilloch, Glasgow, UK John E. Gorton Gorton Systems, Glasgow, UK Robert B. Hammond Institute of Particle Science and Engineering, The University of Leeds, UK RSC Publishing

2 Some Desktop Contents Chapter 1 Introduction The Beginnings History About the Book Some Caveats Getting Started Basics Atoms and Bonds Isomerism, Stereoisomerism, Configuration, and Conformation Low Dimensional Structural Information SMILES in INTERCHEM Where now? 9 References and Endnotes: Chapter 1 10 Chapter 2 Computers for Molecular Modelling Caveats Is Special Computer Equipment Needed? Are there choices to be made? Choice of Operating System Choice of Hardware or Laptop Choices for a Laptop Machine Choices for a Desktop Machine The Other Alternatives The choice of a display The use of a projector for display RAID Computer Systems The Linux Operating Systems Having the Best of Both Worlds Windows and Linux Two or More Machines Dual Boot Machines The Windows Subsystem for UNIXbasedApplications Using Cygwin Virtual Machines Clusters of Computers Networking Security Compatibility of 32Bit and 64Bit operating systems Further Reading 25 References and Endnotes: Chapter 2 26 Chapter 3 Software for Molecular Modelling and Computational Chemistry Chemical Structure and Molecular Modelling Structures obtained from experimental methods The BornOppenheimer principle Molecular Mechanics Molecular mechanics the basics 32

3 how limitations basics geometric X Molecular Modelling: Computational Chemistry Demystified Force field parameters Molecular mechanics Molecular mechanics it works The choice of force fields The extended use of molecular mechanics Method based on quantum mechanics Semiempirical molecular orbital programs Ab initio molecular orbital methods Methods based on density functional theory Basis sets Internal coordinates and Z matrices Atomic units Scaling in computational programs Graphical display software The requirements of molecular modelling How OpenGL satisfies these requirements Molecular modelling software suppliers 45 References and Endnotes: Chapter 3 46 " 39 Chapter 4 Using INTERCHEM for Molecular Modelling Some words of advice Building structures Using INTERCHEM Sketch INTERCHEM Sketch Modifying your drawing Using INTERCHEM Sketch aliphatic structures Generating structures using SMILES strings Accessing the SMILES facility Building structures from fragments Using the INTERCHEM merge tool for building The reliability of structures obtained by building Refining a structure using quantum mechanics (quinine) Getting the energies of structures using quantum mechanics Getting structures from the published literature Getting structures from Xray crystallographic data Information from Xray crystallographic data files Analyzing Structures Bond lengths Inter atomic distances Bond angles Torsion angles Pseudo torsion angles Inter planar angles Molecular mechanic calculations measurement Molecular volume Molecular formula and molecular weight Hydrophobicity 83

4 Contents xi 4.6 Stereochemistry Geometric isomerism (cis/trans or E/Z isomerism) The use of random numbers in INTERCHEM Problems for you to solve, and questions for you to answer 84 References and Endnotes: Chapter 4 86 Chapter 5 Molecular Modelling of Proteins and Nucleic acids Introduction The nature of proteins The structure of proteins The structures of nucleic acids Further reading Obtaining Structures for Proteins and Nucleic Acids Accessing the Protein Data Bank The options provided by the program PROTEINS How the extra data is stored in INTERCHEM 'D' Files 106 and nucleic acids structures Displaying proteins Editing Protein and Nucleic Acid Structures Analyzing Protein Structures Protein Sequences Some Definitions Sequence Matching Background of Aligning Protein Sequences The program PRESTO Introductory exercise Aligning sequence Sets Globally and Locally Questions arising from the alignment experiments Making inferences from alignments Storing images from the screen in PRESTO Racemic protein crystals as sources of protein structures Problems for you to solve and questions for you to answer General instructions applicable to most of these problems 125 References and Endnotes: Chapter Chapter 6 Essentials of Stereochemistry and Conformational Analysis Chirality Conformation and conformational analysis Isomerism involving double bonds and rings Chirality in biphenyl derivatives and allenes 139 References and Endnotes: Chapter Chapter 7 Molecular Modelling and the Solid State of Materials Introduction Classification ofsolids Crystallography and the specification of crystalline structures The lattice concept The crystal lattice in two dimensions The crystal lattice in three dimensions Examining crystal structures with INTERCHEM 156

5 xii Molecular Modelling: Computational Chemistry Demystified Chirality and crystallography Origin of cohesive forces in solids Thermodynamics of crystalline solids and molecular modelling Lattice energy calculations Worked example calculation for sodium sulfate Lattice energy calculations for organic molecular materials The shape of crystals BFDH approach for crystal habit prediction Potential deficiencies in the BFDH approach Attachment energy approach for habit prediction Envoi 182 References and Endnotes: Chapter Chapter 8 The Source of Archived 3D Chemical Structure Information Introduction Structures of small organic molecules from Xray crystallography Structures of inorganic compounds and metals The Protein Databank ZINC Interprobe Chemical Services 3D Database File formats XR Format TRIPOS MOL2 Format PDB format MDL format Crystallographic Information Files (CIF format) INTERCHEM D format Multistructure files General comments about files of 3D coordinates Right handed coordinate systems The rules of engagement 205 References and Endnotes: Chapter Chapter 9 Molecular Modelling and Medicinal Chemistry The need for new (legal) drags Recent history The economics of drug development The plight of pharma What makes a compound a drug The way drugs work a basic classification How modern drugs are designed Some definitions Natural products as leads How molecular modelling helps drug design The drug design pathway High throughput screening Molecular modelling in drug design Virtual high throughput screening Docking 215

6 Variations Contents xiii Additional filtering processes Isosteres on a theme 219 References and Endnotes: Chapter Chapter 10 Using Interprobe Software for Drug Discovery Overview Setting up the database using Cygwin The importance of the full stop (and some other hints) How the databases are organised Setting up the databases for use by QUICKSCAN Using QUICKSCAN Viewing the structures extracted using INTERCHEM Docking experiments using INTERCHEM Getting the necessary files Docking of the ligand into the protein Docking of analogues of tamoxifen Generating series of ligands for docking experiments Other targets for tackling malaria Drugs from natural products Problems for you to solve Envoi 251 References and Endnotes: Chapter Appendices 253 Appendix Al Mathematical Background 254 Appendix A2 Data Tables 261 A2.1 Table of Standard Bond lengths 261 A2.2 Crystallographic Space Groups 262 Appendix A3 Numbering of Steroid Structures 265 Appendix A4 Essential Information for mounting Interprobe software 267 A4.1 Software that is included on the compact disc 267 A4.2 Copying the contents of the CD onto your computer 267 A4.3 Setting up the program INTERCHEM 267 A4.3.1 Testing the program INTERCHEM 267 A4.3.2 Problems due to mismatched dynamic linked libraries 268 A4.3.3 Problems due to the file STEER.DAT 269 A4.3.4 Errors due to the settings on your display screen 270 A4.3.5 Errors in other display parameters 270 A4.4 Setting up the program PRESTO 271 A4.4.1 Testing the program PRESTO 271 A4.4.2 Problems in running PRESTO 271 A4.4.3 Effects of screen resolution on PRESTO 271 A4.4.4 Effects of other screen settings when using PRESTO 271 A4.5 Setting up the other Interprobe programs 273 A4.6 Setting up other programs 274 A4.6.1 Setting up MOPAC 274

7 xiv Molecular Modelling: Computational Chemistry Demystified A4.6.2 Miscellaneous programs and scripts 275 A4.7 Other problems errors in the programs 275 A4.8 Removing and updating Interprobe software on your computer 276 References and Endnotes: Appendix A4 276 Appendix A5 File Compression and Transfer of Files between Computers 277 A5.1 File compression 277 A5.2 Transfer of files between computers and operating systems 278 Answers to 'Problems for you to solve and questions for you to answer' 279 Chapter Chapter Chapter Subject Index 287