Solving Structure Based Design Problems using Discovery Studio 1.7 Building a Flexible Docking Protocol
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1 Solving Structure Based Design Problems using Discovery Studio 1.7 Building a Flexible Docking Protocol C. M. (Venkat) Venkatachalam Fellow, Life Sciences Dipesh Risal Marketing, Life Sciences
2 Overview Flexible Docking elements and challenges Key Pipeline Pilot Components used in Flexible Docking Validation of Components Example workflow for Flexible Docking Validation of workflow Work in progress
3 Flexible Docking (aka Induced Fit ) Input Three dimensional structure of protein 2D structure of a ligand Output Generate docked ligand poses Challenges Forcefield, Scoring Ligand conformational sampling Ligand position and orientational sampling Flexibility of Protein Side chain variations, local and global Large movements of protein chain Placement of water Many of these challenges are addressed in DS 1.7 with wellvalidated and published algorithms The well-validated CHARMm Forcefield and engine underlies all algorithms
4 Value of Flexible Docking Experimental evidence shows that there are variations in protein structure observed when different ligands are bound in it. Virtual high-throughput screening generally employs a single receptor structure with a wide variety of ligands. Ignoring protein flexibility can lead to erroneous docking results. Protein flexibility may play a vital role in the mechanism (pathway) of ligand docking. Thymidine Kinase:1kim complex from xray
5 Variation in Side chains in Estrogen: 1err vs 3ert Δchi = chi(3ert) -chi(1err) residue Δchi1 Δchi2 LEU LEU THR ARG LEU GLU ILE TRP ARG MET HIS LEU LEU TYR ASP LEU err 3ert
6 Discovery Studio and Pipeline Pilot The Flexible Docking protocol requires a Pipeline Pilot Client Can be run in Pipeline Pilot or Discovery Studio 1.7
7 In this presentation We introduce 3 Pipeline Pilot components and a Flexible Docking workflow ChiRotor We show that ChiRotor correctly reconstructs selected side chains with/without ligand present ChiFlex We show that this adequately identifies flexible residues in the binding site and generates a representative set of protein structures with diverse side chain conformations for docking considerations CDOCKER We show that this successfully docks ligands when correct side chain conformations are present Flexible Docking Workflow We show this workflow produces correct ligand poses in several protein systems using both native and cross docking.
8 Key Components used to build a Flexible Docking Workflow Protein w/wout ligand Protein Protein (ChiRotor) Side Chain Builder (ChiFlex) Side Chain Conformations + Ligand CDOCKER Protein structure with only side chain conformations refined Set of protein structures with diverse side chain conformations A set of ligand poses docked into the rigid protein ChiRotor V. Z. Spassov, L. Yan, P. K. Flook, The Dominant Role of Side-chain Backbone Interactions in Structural Realization of Amino-acid Code. ChiRotor: a Side-chain Prediction Algorithm Based on Side-chain Backbone Interactions, Protein Science 16, 1-13 (2007). CDOCKER G. Wu, D. H. Robertson, C. L. Brooks III and M. Veith, Detailed Analysis of Grid-Based Molecular Docking: A Case Study of CDOCKER- A CHARMm-Based MD Docking Algorithm, J. Comp. Chem. 24, , J. A. Erickson, M. Jalaie, D. H. Robertson, R. A. Lewis and M. Vieth, Lessons in Molecular Recognition: The Effects of Ligand and Protein Flexibility on Molecular Docking Accuracy, J. Med. Chem., 47 (1), 45-55, 2004
9 ChiRotor & ChiFlex Schematic 1 2
10 CDOCKER Schematic
11 Block Diagram of a Flexible Docking Protocol 3D Structure of Protein ChiFlex: Side Chain Conformations n Protein Structures differing in side chain conformations Start: Loop over n Protein Structures Stage 1: Dock Ligand to Protein using CDOCKER 1 ligand pose ChiRotor: Rebuild Side chains Stage 2: Dock Ligand to Protein using CDOCKER Save Ligand Poses and Protein Structure
12 Flexible Docking Workflow in Pipeline Pilot
13 Validation
14 Questions that Validation should address ChiRotor Does ChiRotor ( Side Chain Builder ) find the experimentally known side chain conformations? (It is critical that this produces the correct side chain conformations for the Flexible Docking workflow, since during the CDOCKER step the protein is held rigid with the side chain conformations assigned by ChiRotor.) ChiFlex Does ChiFlex ( Side Chain Conformations ) identify the flexible residues in a protein and generate a set of low energy side chain conformations for further considerations? CDOCKER Does CDocker give reasonable ligand dockings if the correct side chain conformations are present in the receptor?
15 ChiRotor: Does ChiRotor construct the correct side chain conformations if a correct ligand pose is given?
16 ChiRotor: Placement of Side Chains in Thymidine Kinase Structures Complex RMSD (Å) Time (secs) 1e2k e2m e2p ki ki ki ki ki kim qhi ki ki ChiRotor calculation with ligand present RMSD to Crystal Structure side chain coordinates Side chains within 4 angstroms from any ligand atom selected for placement Computing time for Dell M 70 Pentium 2 GHz single processor
17 Side Chain Conformations in HUMAN CDK 2 COMPLEXED WITH THE INHIBITOR STAUROSPORINE -ChiRotor without the ligand 1aq1 ILE VAL LYS VAL PHE GLU PHE LEU HIS GLN ASP GLN ASN LEU ASP Protein shown with Ligand
18 ChiFlex: Does ChiFlex ( Side Chain Conformations ) identify the flexible residues in a protein and generate a set of low energy side chain conformations for further considerations?
19 Identification of Flexible Residues Thymidine Kinase (1kim) His58 Glu83 Ile97 Ile100 Gln125 Tyr132 Arg163 Tyr172 Arg176 Arg222 Glu225 Lowest RMSD to Crystal Side Chains ~1.0 angstroms CDK2 (1aq1) Ile10 Lys33 Phe80 Glu81 Leu83 His84 Gln 85 Asp86 Gln131 Asn132 Leu134 Asp145 Lowest RMSD to Crystal Side Chains ~1.8 angstroms Residues identified by ChiFlex as highly flexible (>2 Å)
20 CDOCKER: Does CDOCKER find the correct ligand pose if the correct protein structure is given?
21 CDOCKER Results: RMSD to 41 Crystal Structures RMSD apu (PENICILLOPEPSIN ) RMSD uvs (Thrombin) RMSD 1htf (hiv protease) 1pgp (Phosphogluconate Dehydrogenase ) Proteins Same Dataset as Erickson et al. J Med Chem (2004) 47:45-55
22 Flexible Docking Workflow: Validation Results
23 Flexible Docking of 1kim ligand into 1kim receptor Xray Ligand is shown in green. Ligand RMSD to xray = 0.8 angstrom
24 Flexible Docking of 1ki4 ligand into 1kim receptor Xray Ligand is shown in green. Ligand RMSD to xray = 1.0 angstrom
25 Flexible Docking Summary Ligand to Xray Ligand (w/wout RMS receptor to flex) XRAY w/wout Receptor Flex native docking cross docking System pdb codes (A, B) ResSel 1 aa bb ab ba Thymidine Kinase 1kim, 1ki4 α / /3.7 Estrogen Receptor 1err, 3ert β / /5.2 CDK2 1aq1, 1dm2 α / /1.6 COX2 1cx2, 3pgh β / /5.1 Neuraminidase 1nsc, 1a4q α / /4.2 Thermolysin 1kr6, 1kjo β / /1.9 HIV-RT 1rth, 1c1c α / /3.1 Factor Xa 1ksn, 1xka β / /8.6 1 ResSel Residue Selection for ChiRotor and ChiFlex α Residues within 3.5Å from Xray Ligand in both ChiRotor and ChiFlex β Residues within 3.5Å from Xray Ligand in ChiFlex and additional residues in ChiRotor
26 Strengths of the Approach ChiRotor ability to reliably predict side chain conformations Very flexible interface Power of modifying the workings by modifying workflow Extendable interface adding LOOPER Docking engine may be replaced Consistent, validated force field CHARMm A rational approach to Ligand Protein interaction problem
27 Further Work in Progress Improving Efficiency by Intelligent Ligand Placement Protein structure refinement during docking More validation over larger dataset Fine tuning parameters of the workflow Number of Protein side chain conformations CDOCKER docking parameters
28 Concluding Remarks 3 Pipeline components (ChiFlex, ChiRotor, CDOCKER) have been constructed and validation results presented. A Flexible Docking protocol employing the 3 components shows promise in handling protein side chain flexibility in Ligand docking. This workflow demonstrates the power and flexibility of the DS platform.
29 Thanks to Accelrys R&D Al Maynard (Structure Based Design) Eric Yan (CHARMm) Jürgen Koska (Flexible Docking Workflow) Lisa Yan (Proteins) Nan-Jie Deng (Simulation, CHARMm) Velin Spassov (ChiRotor, ChiFlex) Paul Flook (Direction) Marketing Sylvia Tara Application Scientists > 25 PhD Scientists world wide participating in validation External Collaboration Charles E. Brooks (CHARMm, CDOCKER)
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