Enhanced Monte Carlo Sampling through Replica Exchange with Solute Tempering

被引:36
作者
Cole, Daniel J. [1 ]
Tirado-Rives, Julian [1 ]
Jorgensen, William L. [1 ]
机构
[1] Yale Univ, Dept Chem, New Haven, CT 06520 USA
基金
美国国家卫生研究院;
关键词
HIV-1; REVERSE-TRANSCRIPTASE; NONNUCLEOSIDE INHIBITORS; OPTIMIZATION; POTENT; PREDICTIONS; DISCOVERY; SYSTEMS; VARIANT; DESIGN; AZOLES;
D O I
10.1021/ct400989x
中图分类号
O64 [物理化学(理论化学)、化学物理学];
学科分类号
070304 ; 081704 ;
摘要
With a view to improving the consistency of free energy perturbation calculations in Monte Carlo simulations of protein-ligand complexes, we have implemented the replica exchange with solute tempering (REST) method in the MCPRO software. By augmenting the standard REST approach with regular attempted jumps in selected dihedral angles, our combined method facilitates sampling of ligand binding modes that are separated by high free energy barriers and ensures that computed free energy changes are considerably less dependent on the starting conditions and the chosen mutation pathway than those calculated with standard Monte Carlo sampling. We have applied the enhanced sampling method to the calculation of the activities of seven non-nucleoside inhibitors of HIV-1 reverse transcriptase, and its Tyr181Cys variant, and have shown that a range of binding orientations is possible depending on the nature of the ligand and the presence of mutations at the binding site.
引用
收藏
页码:565 / 571
页数:7
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