Accelerating Virtual High-Throughput Ligand Docking Screening One - - PowerPoint PPT Presentation
Accelerating Virtual High-Throughput Ligand Docking Screening One Million Compounds Using a Petascale Supercomputer Sally R. Ellingson, PhD Candidate Department of Genome Science and Technology, University of Tennessee Center for Molecular
Department of Genome Science and Technology, University of Tennessee Center for Molecular Biophysics, UT/ORNL Advisor: Dr. Jerome Baudry
(In Conjunction with HPDC12 Delft, Netherlands)
Diller, D. J. and Merz, K. M. (2001), High throughput docking for library design and library prioritization. Proteins, 43: 113–124.
(+) Reproduce correct bound conformation (+) Assign better scores to high-affinity ligands than to decoys (enrichment) (-) Generate scores that correlate with measured binding affinities
http://www.chemistry-blog.com/2012/01/04/tedtalk-medicine-for-the-99-hes-about-99-wrong/
(A) Sally R. Ellingson and Jerome Baudry. High-Throughput Virtual Molecular Docking: Hadoop Implementation of AutoDock4 on a Private Cloud. In Proceedings of the second international workshop on Emerging computational methods for the life sciences (ECMLS '11). ACM, New York, NY, USA, 33-38. DOI=10.1145/1996023.1996028 http://doi.acm.org/10.1145/1996023.1996028. (B) Sally R. Ellingson, Sivanesan Dakshanamurthy, Milton Brown, Jeremy C. Smith, and Jerome Baudry. Accelerating Virtual High-Throughput Ligand Docking: Screening One Million Compounds Using a Petascale Supercomputer. Proceedings of the third international workshop on Emerging computational methods for the life sciences (ECMLS '12) (accepted)
(A) (B)
http://www.chemistry-blog.com/2012/01/04/tedtalk-medicine-for-the-99-hes-about-99-wrong/
Virtual screenings:
chemical compounds
http://autodock.scripps.edu/ Free, open source docking software developed at The Scripps Research Institute Conformational Search using Lamarckian Genetic Algorithm
Morris, G. M., Goodsell, D. S., Halliday, R. S., Huey, R., Hart, W. E., Belew, R. K. and Olson, A. J. (1998), Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J. Comput. Chem., 19: 1639–1662.
http://autodock.scripps.edu/ Free, open source docking software developed at The Scripps Research Institute Scoring of generated conformations
Huey, R., Morris, G. M., Olson, A. J. and Goodsell, D. S. (2007), A semiempirical free energy force field with charge-based desolvation. J. Comput. Chem., 28: 1145–1152.
http://autodock.scripps.edu/ Free, open source docking software developed at The Scripps Research Institute Virtual Docking Process
Precalculated Affinity Grids Receptor PDBQT Ligand PDBQT Docking Parameter File
AutoDock
Docking Log File
This process must be done for every ligand in a high-throughput screening
Task-parallel message passing interface implementation of Autodock4 for docking of very large databases of compounds using high-performance super-computers. B. Collignon, R. Schulz, J.C. Smith and J. Baudry J. Comput. Chem. (2011) 32 (6): 1202–1209
Main Improvements for Virtual Screening
the screening and individual ligands
A high-throughput virtual screening tool Goal
(MPI)
Task-parallel message passing interface implementation of Autodock4 for docking of very large databases of compounds using high-performance super-computers. B. Collignon, R. Schulz, J.C. Smith and J. Baudry J. Comput. Chem. (2011) 32 (6): 1202–1209
A high-throughput virtual screening tool using 196 CPUs maps.h5 19MB -53MB → 9.8MB-28MB
Task-parallel message passing interface implementation of Autodock4 for docking of very large databases of compounds using high-performance super-computers. B. Collignon, R. Schulz, J.C. Smith and J. Baudry J. Comput. Chem. (2011) 32 (6): 1202–1209
A high-throughput virtual screening tool
TUTORIAL http://www.bio.utk.edu/baudrylab/autodockmpi.htm
Sally R. Ellingson, Sivanesan Dakshanamurthy, Milton Brown, Jeremy C. Smith, and Jerome Baudry. Accelerating Virtual High-Throughput Ligand Docking: Screening One Million Compounds Using a Petascale Supercomputer. Proceedings of the third international workshop on Emerging computational methods for the life sciences (ECMLS '12) (accepted)
Workflow controlled by python scripts Runs on Lens (analysis cluster - Jaguar)
Sally R. Ellingson, Sivanesan Dakshanamurthy, Milton Brown, Jeremy C. Smith, and Jerome Baudry. Accelerating Virtual High-Throughput Ligand Docking: Screening One Million Compounds Using a Petascale Supercomputer. Proceedings of the third international workshop on Emerging computational methods for the life sciences (ECMLS '12) (accepted)
65k processors
20000 40000 60000 80000 100000 120000 140000 160000 180000 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 # of compounds Rotatable Bonds (Degrees of Freedom)
Million Compound Library
http://www.chemistry-blog.com/2012/01/04/tedtalk-medicine-for-the-99- hes-about-99-wrong/
Multi- protein docking Many proteins of important function Drug Candidate
Also for many conformations of the same protein – to model receptor flexibility Multi-protein docking:
Multi- protein docking Many proteins of important function Drug Candidate
Autodock4.lga.MPI
What is needed? A tool that allows an increase in the number of receptors used in a screening with a minimal increase in the amount of I/O per docking task
Receptor PDBs Ligand PDBs Multi- protein screening All combinations
step mutation, local optimization, Metropolis acceptance criterion
Trott, O. and Olson, A. J. (2010), AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 31: 455–461. doi: 10.1002/jcc.21334 Average time in minutes per complex 2-quad core processors
Autodock4 Autodock Vina
Scalable Computing and Leading Edge Innovative Technologies