Study of Highly Accurate and Fast Protein-Ligand Docking

Study of Highly Accurate and Fast Protein-Ligand Docking Method Based on Molecular Dynamics M. Taufer, M. Crowley, D. J. Price, A. A. Chien‡ and C. L. Brooks III∗, † Department of Molecular Biology (TPC 6), The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, U. S. A. Reporter: Yu Lun Kuo E-mail: sscc 6991@gmail. com Date: November 21, 2006 Published online 24 June 2005 in Wiley Inter. Science 1

Outline • • • 2 Introduction MD-based Docking Method Algorithm Evaluation Metrics MD vs. Other Methods Conclusion & Future work

Introduction (1/3) • Drug development • Use of small molecules (ligand) to turn on or off a protein function • Protein-ligand docking • Computational methods for the prediction of ligandprotein structure information 3

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. 4

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 5

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 6

MD-based Docking Method (2/2) 20 Docking trial MD Simulation Heating & Cooling phase (300 K 700 K 300 K) Scoring function to rank Lowest energy structure 7

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 – Auto. Dock、DOCK、Flex. X、ICM、GOLD 8

Algorithm Evaluation (2/2) • Experimental testbed – Platform • SGI R 10000 – Single 195 MHz IP 2 processor – 128 MB 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 9

Metrics • Docking Accuracy (DA) – DA = f. RMSD<2 + 0. 5(f. RMSD<3 - f. RMSD<2) – f. RMSD