dockomatic : automated tool for homology modeling and docking studies
DESCRIPTION
Tutorial. DockoMatic : Automated Tool for Homology Modeling and Docking Studies. Learning Objectives. I. Create & validate a protein homology model II. Use molecular docking to calculate the binding energy for a drug to the protein III. Assessment of docking results - PowerPoint PPT PresentationTRANSCRIPT
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DockoMatic:Automated Tool for Homology Modeling and Docking Studies
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
Tutorial
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Learning Objectives
I. Create & validate a protein homology model
II. Use molecular docking to calculate the binding energy for a drug to the protein
III. Assessment of docking results
IV. Visualize the protein-drug complex
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Systems of Interest Protein: Collagen α1 (XI) NPP domain
223 amino acid protein 2 disulfide bonds A minor fibrillar collagen involved in
thrombosis
Drug: Arixtra (a.k.a. Fondaparinux) A heparin-based drug An anticoagulant used to treat blood clots Binds Col α1 (XI) NPP to prevent blood
coagulation O
OO
OO
-O3SO
OH
OH
NHSO3-
O
O O
OH
OH
O
-O3SO
OSO3-
NHOSO3-
O
COO-OH
OSO3-
O
OH
-O3SO
O CH3
NHSO3-
Arixtra structure
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DockoMatic 2.0
User friendly graphical user interface (GUI) for automation
Homology model creation using the Timely Integrated Modeller (TIM) interface
Create, submit, manage AutoDock1 molecular docking calculations
Track jobs & analyze results using PyMol2
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
1. Morris, G. M. et al. J. Computational Chemistry 2009, 16: 2785-91.2. The PyMOL Molecular Graphics System, Version 1.5.0.4 Schrödinger, LLC.
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How many structures solved? The Protein Data
Bank*Dposition Year X-Ray Structures Total X-Ray Structures1995 971 9711996 1148 21191997 1503 36221998 1793 54151999 2149 75642000 2457 100212001 2657 126782002 2782 154602003 3917 193772004 4454 238312005 5131 289622006 5664 346262007 6695 413212008 6115 474362009 7357 547932010 7790 625832011 8308 708912012 3953 74844
*Bernstein, et al. (1977) J. Mol. Biol. 112, 535.
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Part I: Homology Modeling
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Homology Modeling: Overview
Prediction of 3D-structure of a given protein sequence (target) based on alignment to known protein structures (templates)
A useful model requires 30% sequence identity between target and template
Models used to understand function, activity, ligand binding paradigms in drug design, etc.
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
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Homology Model: Template Selection
1. Begin with the target amino acid sequence
2. Use the Basic Local Alignment Search Tool* (BLAST) to search for amino acid sequences of template proteins where the 3D structure is available
3. The principle repository for 3D protein structures is the National Center for Biotechnology Information+ (NCBI)
4. Only amino acid sequences with greater than 30% identity between target and template should be considered.
5. If functionality is known for a class or family of proteins, look to protein templates with similar functionality as the target.
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
*Johnson et al. (2008) Nucleic Acids Res. 36, W5-9. +Edgar, et al. (2002) Nucleic Acids Res. 30, 207-210
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Homology Modeling: Flow Chart
Target Sequence
Model Building for the Target
Template Selection
Alignment (Target-
Template)
Evaluate the
Model
Known (Template) Structures
Homology Model
YESNO
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Homology Model Creation:
DockoMatic Procedure
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• Open Terminal Window
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• Type: ssh –X username@host
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• Enter password
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• This is the HOME directory
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• Type: cd $SCRATCH
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• Type: mkdir DOCKOMATIC-WORKSHOP
• Type: cd DOCKOMATIC-WORKSHOP
• Type: dockomatic
• DockoMatic will now open in a new window
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DockoMatic 2.0 GUI
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DockoMatic
Select:
Use Modeller
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DockoMatic: Accessing the TIM Wizard
Click on:
Receptor Timely
Integrated Modeller (TIM) Wizard will open in a new window
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DockoMatic – TIM Wizard Interface
TIM Wizard
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TIM Step 1: Enter Template Sequence
Click on:
Output Directory
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TIM Step 1 (cont’d): Sequence Entry
Select: The desired output directory
Click: OK
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Output directory path is now established
Note this path for future reference
TIM Step 1 (cont’d): Sequence Entry
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Click on:
‘Sequence’
Choose the target .pdb file
OR
Copy/Paste Sequence:
If you don’t have a .pdb, you can copy & paste the sequence here.
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TIM Step 1 (cont’d): Sequence Entry
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Name the target sequence
Click: Next
TIM Step 1 (cont’d): Sequence Entry
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TIM Step 2: Search for a Template
BLAST Template Search
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Template list BLAST
output
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TIM Step 2 (cont’d): Template List
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Select a template
Templates listed from highest match to lowest
Click: Next
TIM Step 2 (cont’d): Template Selection
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TIM Step 3: Sequence Alignment
Alignment in progress
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Select sequence of template that has been aligned with the target
TIM Step 3: Select Aligned Sequence
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Aligned template and target sequence display.
Alignment may be edited in this window.
Click: Next
TIM Step 4: Edit Aligned Sequence
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TIM Step 5: Model Generation
Model generation in progress
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List of homology models for target protein created based on template structure
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TIM Step 5: List of Models Created
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Select a homology model
Models listed from best to worst correlation
Click: Finish
TIM Step 5: Select Homology Model
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Receptor field shows selected homology model.
Do not close this window; it will be required for molecular docking.
End TIM Wizard: 3D Model for MD
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• Open a terminal window.
• Enter output directory path (you noted this earlier).
• Type: ls
• The content of the working directory contains the .pdb files of the homology models for the target protein along with all other output files generated by DockoMatic.
Location of Model Structure Files
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Homology Model Validation
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HM Validation: Ramachandran Plot• Model assessment using
RAMPAGE1 webserver
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking1. http://mordred.bioc.cam.ac.uk/~rapper/rampage.php
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HM Validation: Sequence Alignment
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HM Validation: Structure Overlay
Homology modelfor Col α1 (XI) NPP
PDB ID: 2UUR Template
Root mean square deviation of Cα atoms = 1.12 Å
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Part II: Grid Parameter File Creation
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Open AutoDockTools
(ADT)• In the terminal type:
• adt &
• Click on the Icon created at installation
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• Click on: Grid
• Then click ‘Macromolecule’ in the popup menu, then ‘Open…’
• You can either load a .pdb or a .pdbqt created from an earlier ADT use.
• Change the file type to ‘.pdb’, unless loading the .pdbqt file type.
• Choose your file, then click open.
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• The file will load then imidiately ask you to choose a location to save the converted .pdbqt
• Choose your location and filename, then click save
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• Click on: Grid
• Then click ‘Grid Box…’ in the popup menu
• This allows you to define the area of interest in the molecule. It is described by xyz coordinates. The molecule can be rotated by clicking and dragging.
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• Click on: Grid
• Then click ‘Output’ in the popup menu, then ‘Save GPF…’
• Choose your location and filename, then click save
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Part III: Molecular Docking
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Molecular Docking: Background
Docking : Molecular simulation of a ligand binding to a receptor
Output: Binding energies & scoring functions
Visualization: Binding poses for ligands Docking tools
AutoDock DOCK Glide MOE GOLDDOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
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Force Fields for Autodock Energy Function
http://autodock.scripps.edu/resources/science/equations/
ΔGH-bond = WH-bond ∑i, j E(t) * ( Cij / rij12 - Dij / rij
10 + Ehbond )
ΔGvdW = WvdW ∑i, j ( Aij / rij12 - Bij / rij
6 )
ΔGelec = Welec ∑i, j ( qi * qj ) / ( ε(rij) * rij )
ΔGdesolv = Wdesolv ∑i (C), j (Si * Vj * exp ( -rij2 / (2 * σ2) ) )
ΔGtor = Wtor Ntor
ΔG = ΔGvdW + ΔGH-bond + ΔGelec + ΔGtor +
ΔGdesolv
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Molecular Docking: Protocol
http://Autodock.scripps.edu
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Click: Output Directory
Molecular Docking in DockoMatic
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Select output directory
Click: OK
MD: Getting Started
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Click: Ligand
MD Step 1: Selecting a Ligand
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Select a ligand structure file (arixtra.pdb)
Click: OK
MD Step 1 (cont’d): Ligand Selection
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Click: Receptor
MD Step 2: Receptor Selection
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Select the homology model of Col α1 (XI) NPP from part 1 as the receptor
Click: OK
MD Step 2 (cont’d): Receptor Selection
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Click: Box Coordinates
MD Step 3: Receptor Binding Site Selection
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Select a box coordinate file
Click: OK
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MD Step 3 (cont’d): Receptor BindingSite Selection
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Select number of AutoDock jobs to run: default=100; for this exercise select 10
Click: New Job
MD Step 4: Job Setup
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Your job is not yet started
Job status displayed here
MD: Job Status
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Left mouse click to select
Right click to access menu
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MD: Starting the Docking Jobs
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StartDeleteAnalyzeView in PyMOl
Right click initiates pop-up window
MD: Starting the Docking Jobs (cont’d)
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
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StartDeleteAnalyzeView in PyMOl
Click: Start to submit jobs
While jobs are running, review input and output files.
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
MD: Starting the Docking Jobs (cont’d)
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• Return to terminal window and type ‘ls’ to list files
• Make sure path is correct; if not, use ‘cd’ to change directory
• Starting a job creates dock directories where results are located
• Type: cd dock_1
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
Review Files in Terminal Window
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Part IV: Assessment of Docking Results
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
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• Result output files
• Type: more arixtra.pdbqt
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
Viewing the Contents of a Structure File
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• arixtra.pdbqt contents
• Type: q
• Type: more dock.gpf
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
Protein Data Base File for Arixtra
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• dock.gpf contents
• Type: more dock.dpf
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
Viewing the Contents of a Grid Parameter File
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• View the contents of the dock.dpf file
• Type: more dock.dpf
Viewing the Contents of a Docking Parameter File
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
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DockoMatic: MD Required Files
DockoMatic automation requires a receptor, ligand, and grid parameter file as input
GPF creation: To run an autogrid job you would type:
autogrid4 –p dock.gpf –l _gridLog.glg &
*****You need not to run autogrid job*****
To run an autodock job you would have to type:
autodock4 –p _.dpf –l _dockLog.dlg &
*****You need not to run autodock job*****
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• Check gridLog file
• Type: tail -100 _gridlog.glg
• _gridlog.glg end of file contents (last 100 lines)
• This means autogrid completed successfully
DockoMatic: Grid Parameter Files
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
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• Check dockLog
• Type: tail -100 _docklog.dlg
• _docklog.dlg end of file contents (last 100 lines)
• This means autodock completed successfully
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
DockoMatic: Job Status in Terminal
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• To check the Cluster Histogram data
• Type: less _docklog.dlg
• Scroll down a long way until you get to the Clustering Histogram section.
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
MD Result Analysis: Cluster Histogram
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Part VV Visualize the Protein-Ligand Complex
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
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Left mouse click to select
Right click to display the menu
Viewing MD Results
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
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StartDeleteAnalyzeView in PyMOl
Click:
View in PyMOL
A 3D model viewer should open in a new window
MD Result Analysis: Visualization
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
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Select the top ranked result
Click: OK
MD Analysis: Selecting a Result
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
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Open PyMol Click: File, then
Open This will open the
arixtra_rank_1.pdb file.
This is the ligand binding pose for the lowest energy docked complex
MD Analysis in PyMOL
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
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Select a protein structure file
Click: Open This will
provide the structure of the protein receptor molecule
PyMOL: View Protein Receptor
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
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3D protein structure
Homology model of Col α1 (XI) NPP
Protein Structure Viewed in PyMOL
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
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Collagen α1 (XI) NPP domain
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
Ribbon Structure of Protein in PyMOL
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Protein-Ligand Complex in PyMol
Arixtra
Lowest Ki = -6.51 kcal/mol
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PyMol View of Protein-Ligand Interactions
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
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Close up View of Interactions between Arixtra and Binding
Site Residues
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
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Conclusions
DockoMatic Homology model
Model Creation Structure Validation
Molecular docking Docking Studies Result Analysis
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking
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Questions!&
Thank You
DOCKOMATIC-Student Procedure-Homology Modeling & Molecular Docking