High-Throughput All-Atom Molecular Dynamics Simulations Using Distributed Computing

被引:150
作者
Buch, I. [1 ]
Harvey, M. J. [2 ]
Giorgino, T. [1 ]
Anderson, D. P. [3 ]
De Fabritiis, G. [1 ]
机构
[1] Univ Pompeu Fabra, Computat Biochem & Biophys Lab GRIB IMIM, Barcelona 08003, Spain
[2] Univ London Imperial Coll Sci Technol & Med, High Performance Comp Serv, London SW7 2AZ, England
[3] Univ Calif Berkeley, Space Sci Lab, Berkeley, CA 94720 USA
基金
美国国家科学基金会;
关键词
FREE-ENERGY; SH2; DOMAIN; BINDING; LIGAND; ENERGETICS;
D O I
10.1021/ci900455r
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Although molecular dynamics simulation methods are useful in the modeling of macromolecular systems, they remain computationally expensive, with production work requiring costly high-performance computing (HPC) resources. We review recent innovations in accelerating molecular dynamics on graphics processing units (GPUs), and we describe GPUGRID, a volunteer computing project that uses the GPU resources of nondedicated desktop and workstation computers. In particular, we demonstrate the capability of simulating thousands of all-atom molecular trajectories generated at an average of 20 ns/day each (for systems of similar to 30 000-80 000 atoms). In conjunction with a potential of mean force (PMF) protocol for computing binding free energies, we demonstrate the use of GPUGRID in the computation of accurate binding affinities of the Src SH2 domain/pYEEI ligand complex by reconstructing the PMF over 373 umbrella sampling windows of 55 ns each (20.5 mu s of total data). We obtain a standard free energy of binding of -8.7 +/- 0.4 kcal/mol within 0.7 kcal/mol from experimental results. This infrastructure will provide the basis for a robust system for high-throughput accurate binding affinity prediction.
引用
收藏
页码:397 / 403
页数:7
相关论文
共 28 条
[1]  
Anderson DR, 2006, AMER PHILOS SER, P33, DOI 10.1109/SC.2006.24
[2]   Calorimetric investigation of proton linkage by monitoring both the enthalpy and association constant of binding: Application to the interaction of the Src SH2 domain with a high-affinity tyrosyl phosphopeptide [J].
Bradshaw, JM ;
Waksman, G .
BIOCHEMISTRY, 1998, 37 (44) :15400-15407
[3]   PARTICLE MESH EWALD - AN N.LOG(N) METHOD FOR EWALD SUMS IN LARGE SYSTEMS [J].
DARDEN, T ;
YORK, D ;
PEDERSEN, L .
JOURNAL OF CHEMICAL PHYSICS, 1993, 98 (12) :10089-10092
[4]   Energetics of K+ permeability through Gramicidin A by forward-reverse steered molecular dynamics [J].
De Fabritiis, G. ;
Coveney, P. V. ;
Villa-Freixa, J. .
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, 2008, 73 (01) :185-194
[5]   Insights from the energetics binding at the domain-ligand of the Src SH2 domain of water interface [J].
De Fabritiis, Gianni ;
Geroult, Sebastien ;
Coveney, Peter V. ;
Waksman, Gabriel .
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, 2008, 72 (04) :1290-1297
[6]   Computations of Standard Binding Free Energies with Molecular Dynamics Simulations [J].
Deng, Yuqing ;
Roux, Benoit .
JOURNAL OF PHYSICAL CHEMISTRY B, 2009, 113 (08) :2234-2246
[7]   Standard Free Energy of Binding from a One-Dimensional Potential of Mean Force [J].
Doudou, Slimane ;
Burton, Neil A. ;
Henchman, Richard H. .
JOURNAL OF CHEMICAL THEORY AND COMPUTATION, 2009, 5 (04) :909-918
[8]   A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations [J].
Duan, Y ;
Wu, C ;
Chowdhury, S ;
Lee, MC ;
Xiong, GM ;
Zhang, W ;
Yang, R ;
Cieplak, P ;
Luo, R ;
Lee, T ;
Caldwell, J ;
Wang, JM ;
Kollman, P .
JOURNAL OF COMPUTATIONAL CHEMISTRY, 2003, 24 (16) :1999-2012
[9]   In silico pharmacology for drug discovery:: methods for virtual ligand screening and profiling [J].
Ekins, S. ;
Mestres, J. ;
Testa, B. .
BRITISH JOURNAL OF PHARMACOLOGY, 2007, 152 (01) :9-20
[10]  
Feenstra KA, 1999, J COMPUT CHEM, V20, P786, DOI 10.1002/(SICI)1096-987X(199906)20:8<786::AID-JCC5>3.0.CO