Prime User Manual - Hom | Hom

[Pages:160]Prime User Manual

Prime 3.1

User Manual

Schr?dinger Press

Prime User Manual Copyright ? 2012 Schr?dinger, LLC. All rights reserved.

While care has been taken in the preparation of this publication, Schr?dinger assumes no responsibility for errors or omissions, or for damages resulting from the use of the information contained herein.

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Revision A, September 2012

Contents

Document Conventions ..................................................................................................... xi

Chapter 1: Introduction ....................................................................................................... 1

1.1 The Prime Suite in Maestro ..................................................................................... 1 1.2 Prime Documentation ............................................................................................... 3 1.3 Running Schr?dinger Software .............................................................................. 4 1.4 Citing Prime in Publications.................................................................................... 6

Chapter 2: Using Prime?Structure Prediction .................................................... 7

2.1 Prime Runs and Maestro Projects.......................................................................... 7 2.2 General Panel Layout................................................................................................ 8 2.3 The Menu Bar ........................................................................................................... 10

2.3.1 The File Menu ................................................................................................... 10 2.3.2 The Edit Menu................................................................................................... 11 2.3.3 The Display Menu ............................................................................................. 11 2.3.4 The Step Menu ................................................................................................. 14 2.4 The Prime Toolbar ................................................................................................... 14 2.5 The Prime Sequence Viewer.................................................................................. 15 2.6 Prime Job Options and Control ............................................................................ 18 2.6.1 The Job Options Dialog Box ............................................................................. 18 2.6.2 Setting Up and Launching Jobs ........................................................................ 18 2.6.3 Monitoring Jobs................................................................................................. 19 2.6.4 Adding Structures to the Project Table.............................................................. 19

Chapter 3: Structure Prediction: Initial Steps.................................................... 21

3.1 Input Sequence Step............................................................................................... 21 3.2 Find Homologs Step ............................................................................................... 23

3.2.1 Importing Homologs.......................................................................................... 23 3.2.2 Searching for Homologs.................................................................................... 23 3.2.3 Find Homologs Search Options ........................................................................ 25

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3.2.4 Search Results.................................................................................................. 26 3.2.5 Multiple Templates and Structure Alignment..................................................... 29 3.2.6 Continuing to the Next Step .............................................................................. 30 3.2.7 Saving Runs With Different Templates.............................................................. 30

Chapter 4: Structure Prediction--Edit Alignment........................................... 31

4.1 Overview of the Edit Alignment Step................................................................... 31 4.2 Using Existing Alignments .................................................................................... 31 4.3 Generating an Alignment ....................................................................................... 33

4.3.1 Generating SSPs .............................................................................................. 33 4.3.2 Importing and Exporting SSPs ......................................................................... 33 4.3.3 Adjusting SSPs ................................................................................................. 34 4.3.4 Running the Alignment...................................................................................... 35 4.3.5 Align Program Technical Details ....................................................................... 36 4.4 Manually Editing an Alignment ............................................................................. 37 4.5 Error Messages........................................................................................................ 37

Chapter 5: Structure Prediction--Build Structure .......................................... 39

5.1 The Build Process ................................................................................................... 39 5.2 Choosing the Model Type ...................................................................................... 39

5.2.1 Building a Composite Model ............................................................................. 40 5.2.2 Building a Consensus Model ............................................................................ 41 5.2.3 Building Multimers............................................................................................. 41 5.3 Preparing to Build ................................................................................................... 42 5.3.1 Setting Constraints............................................................................................ 42 5.3.2 Including Ligands and Cofactors....................................................................... 42 5.3.3 Build Options..................................................................................................... 42 5.4 Building the Structure ............................................................................................ 44 5.5 Technical Notes for the Build Structure Step..................................................... 45

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Chapter 6: Refining Protein Structures ................................................................. 47

6.1 Preparing Structures for Refinement................................................................... 47 6.2 Using the Refinement Panel .................................................................................. 51 6.3 Setting Up an Implicit Membrane ......................................................................... 52 6.4 Refining Loops......................................................................................................... 54 6.5 Predicting Side Chains........................................................................................... 56 6.6 Minimizing Structures ............................................................................................ 57 6.7 Analyzing the Energy.............................................................................................. 58 6.8 Setting Refinement Options .................................................................................. 58

6.8.1 General Options................................................................................................ 59 6.8.2 Dielectric Options.............................................................................................. 59 6.8.3 Side-Chain Prediction Options.......................................................................... 60 6.8.4 Loop Refinement Options ................................................................................. 61 6.9 Applying Constraints.............................................................................................. 63 6.10 Technical Details for Refinement ....................................................................... 66 6.10.1 Loop Refinement............................................................................................. 66 6.10.2 Cooperative Loop Refinement ........................................................................ 67 6.10.3 Side-Chain Prediction ..................................................................................... 68 6.11 Refinement with Nonstandard Residues .......................................................... 69 6.12 Output of Refinement Jobs ................................................................................. 69

Chapter 7: Maestro Protein Structure Alignment ........................................... 71

7.1 The Protein Structure Alignment Panel............................................................... 71 7.2 The Align Binding Sites Panel .............................................................................. 73

Chapter 8: Docking Covalently Bound Ligands ............................................... 77

8.1 Running Covalent Docking from Maestro........................................................... 77 8.1.1 Selecting the Ligands........................................................................................ 78 8.1.2 Defining the Ligand Reactive Groups ............................................................... 79

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8.1.3 Specifying the Receptor Bond to Break ............................................................ 79 8.1.4 Specifying Receptor Residues to Sample......................................................... 80 8.1.5 Setting the Number of Output Poses ................................................................ 80 8.1.6 Running the Job................................................................................................ 80 8.1.7 Output ............................................................................................................... 81 8.2 Running Covalent Docking from the Command Line ....................................... 81

Chapter 9: Prime MM-GBSA ........................................................................................ 83

9.1 Running Prime MM-GBSA from Maestro ............................................................ 83

9.2 Running Prime MM-GBSA from the Command Line......................................... 85 9.2.1 Command Input File.......................................................................................... 88 9.2.2 ASL Expressions............................................................................................... 88

9.3 Prime MM-GBSA Output ........................................................................................ 88

Chapter 10: Command Syntax.................................................................................... 91

10.1 blast--Run Blast Searches.................................................................................. 91 10.2 prime--Build and Refine Protein Structures.................................................... 94

10.2.1 Command Input File........................................................................................ 94 10.2.2 Constraint Syntax.......................................................................................... 103 10.2.3 Restarting an Incomplete Loop Refinement Job........................................... 104 10.2.4 Environment Variables .................................................................................. 104 10.2.5 Examples ...................................................................................................... 105

10.2.5.1 Model Building ................................................................................... 105 10.2.5.2 Energy calculation.............................................................................. 105 10.2.5.3 Side-Chain Prediction ........................................................................ 106 10.2.5.4 Minimization ...................................................................................... 106 10.2.5.5 Loop Prediction.................................................................................. 106 10.3 ska--Protein Structure Alignment ................................................................... 107

10.4 ssp--Secondary Structure Prediction............................................................. 112 10.5 sta--Single Template Alignment ...................................................................... 113

10.6 tfm--Tertiary Folding Module ........................................................................... 116

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Chapter 11: Command-Line Utilities ..................................................................... 119

11.1 Multiple Template Alignment: structalign....................................................... 119 11.2 Format Conversion: seqconvert....................................................................... 121 11.3 Structure Alignment: align_binding_sites...................................................... 122 11.4 Database Update Utilities .................................................................................. 124

11.4.1 update_BLASTDB......................................................................................... 124 11.4.2 rsync_pdb ..................................................................................................... 125

Appendix A: Third-Party Programs ........................................................................ 127

A.1 Location of Third-Party Programs .................................................................... 127 A.1.1 BLAST/PSI-BLAST, Pfam, and the PDB......................................................... 127 A.1.2 Secondary Structure Prediction...................................................................... 128

A.2 Third-Party Program Use Agreement ............................................................... 128

Appendix B: Environment Variables ...................................................................... 129

Appendix C: File Formats ............................................................................................. 131

C.1 Input File Formats ................................................................................................ 131 C.2 Output File Formats ............................................................................................ 131

Appendix D: Error Messages and Warnings ................................................... 133

D.1 Input Sequence .................................................................................................... 133 D.2 Find Homologs ..................................................................................................... 133

D.2.1 Error Messages .............................................................................................. 133 D.2.2 Warnings in Homologs Table .......................................................................... 134 D.3 Edit Alignment ...................................................................................................... 135 D.4 Build Structure ..................................................................................................... 135 D.5 Refinement ............................................................................................................ 135

Getting Help ........................................................................................................................... 137

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Glossary.................................................................................................................................... 141 Index ............................................................................................................................................ 143

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