1/20 study of highly accurate and fast protein-ligand docking method based on molecular dynamics...
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Study of Highly Accurate and Fast Protein-Ligand Docking Method Based on Molecular Dynamics
Reporter: Yu Lun KuoE-mail: [email protected]: November 21, 2006
M. Taufer, M. Crowley, D. J. Price, A. A. Chien‡ and C. L. Brooks III ,∗†
Department of Molecular Biology (TPC6), The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, U.S.A.
Published online 24 June 2005 in Wiley InterScience
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Outline
• Introduction
• MD-based Docking Method
• Algorithm Evaluation
• Metrics
• MD vs. Other Methods
• Conclusion & Future work
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Introduction (1/3)
• Drug development• Use of small molecules (ligand) to turn on or off a protei
n function
• Protein-ligand docking• Computational methods for the prediction of ligand-prot
ein structure information
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Introduction (2/3)
• Exiting docking method– Current docking algorithms are fast and use simplified
scoring function to direct conformational search and select the best structure
– Methods based on molecular dynamics (MD) and atomically detailed force field (e.g., CDOCKER) are more accurate but time- and resource-expensive.
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Introduction (3/3)
• Desktop grids– By scavenging for available and idle cycles
– Provide computing power at a significant cost saving
• Our algorithm– Parallel and each simulation attempt is decomposable
into independent sub-jobs
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MD-based Docking Method (1/2)
• Goals– Assure accuracy
• Benefit from the molecular mechanics force fields
– Guarantee performance • Return docking results in a short turnaround time using
cost-effective platforms
• Approach– Docking method based on CHARMM molecular
dynamics simulations and with a highly flexible computational granularity
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MD-based Docking Method (2/2)
MD SimulationHeating & Cooling
phase (300K700K300K)
Scoring function to rankLowest energy structure
20 Docking trial
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Algorithm Evaluation (1/2)
• Characterization of the docking method:– Does the MD length affect the docking accuracy?
– Does the number of trials affect the docking accuracy?
• Comparing algorithm with other well-known docking methods– AutoDock 、 DOCK 、 FlexX 、 ICM 、 GOLD
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Algorithm Evaluation (2/2)
• Experimental testbed– Platform
• SGI R10000 – Single 195MHz IP2 processor– 128MB memory
• A cluster of 64 dual-processor nodes at the SDSC (San Diego Supercomputer Center)
– Data set: 31 protein-ligand complexes• 10 proteins• 31 ligands with different levels of complexity
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Metrics
• Docking Accuracy (DA)– DA = fRMSD<2 + 0.5(fRMSD<3 - fRMSD<2)
– fRMSD<a fraction of predicted ligands docked into a given protein with RMSD lesser or equal to a Ǻ
• Computational Time– Time to complete a set of docking trials
– Report CPU time for sets of 1, 10 and 20 trials
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Four Different MD Simulations
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Docking Accuracy (DA)
Ten trials per attempt ensure
enough accuracy(T10)
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Average Time with Different Number of MD Steps
Increase of number of MD steps
Almost linear increase of the simulation time
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MD vs. Other Methods
• Other Methods– AutoDock 、 DOCK 、 FlexX 、 ICM 、 GOLD
• Comparison Metrics– Docking Accuracy (DA)
– RMSD of predicted ligands
– CPU time per attempt
• Definition of attempt– Consider CASE B and 10 trials per attempt (T10)
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Comparison of Docking Accuracy
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Best RMSD of Predicted Ligands
RMSD: Root-mean-square-deviation
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Time ComparisonIf enough processors are available, the time for completing a protein-ligand docking is competitive with the other methods
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Conclusion & Future work
• The MD-based docking method– Reach an average accuracy of 71%
• Still a lot of exciting research has to be addressed both at the application and system levels– Number of ligand orientations per trial based on r
esources and node reliability
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Conclusion & Future work
• Future work– Plan to make a more detailed study of MD and
Monte Carlo simulations for the docking process in the near future.
• ICM running multiple Monte Carlo minimizations
• Our docking protocol to desktop grids– Proportionally decreases the time to solution
– Fine-grained parallel algorithm for docking trial
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Thanks for your attention