Rapid alchemical free energy calculation employing a generalized born implicit solvent model.
Rapid alchemical free energy calculation employing a generalized born implicit solvent model.
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DOI：
10.1021/jp506367y
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发表时间：
2015-01
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影响因子：
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通讯作者：
Katja Ostermeir;M. Zacharias
中科院分区：
文献类型：
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作者：
Katja Ostermeir;M. Zacharias
广义Born（GB）隐式溶剂模型通常用于对从显式溶剂模拟获得的分子动力学轨迹进行后处理，以估计蛋白质中的结合自由能或突变的影响。采用GB隐式溶剂模型的可能性进行了探讨，严格的自由能变化的计算与炼金术的转变。在自由能微扰（FEP）模拟过程中，Lennard-Jones，库仑和玻恩半径参数逐渐转化为一个单一的拓扑序列。FEP计算嵌入在一个副本交换计划，允许快速收敛。该方法进行了测试上的相对水合自由能，相对结合自由能的配体-受体系统的计算，并在硅丙氨酸扫描的肽-蛋白质复合物。在所有的情况下，与现有的实验数据得到了良好的协议。在中等大小的蛋白质配体系统，并使用一个集群的图形处理单元，该方法允许计算的相对自由能的变化与化学修饰的结合伙伴在几分钟内的计算机时间，并打开了系统的可能性在硅片研究。
Generalized Born (GB) implicit solvent models are typically used in postprocessing of molecular dynamics trajectories obtained from explicit solvent simulations to estimate binding free energies or effects of mutations in proteins. The possibility to employ a GB implicit solvent model for the calculation of rigorous free energy changes associated with alchemical transformations has been explored. During free energy perturbation (FEP) simulations, Lennard-Jones, Coulomb, and Born radii parameters are transformed gradually in a single-topology series. The FEP calculations are embedded in a replica exchange scheme allowing rapid convergence. The method was tested on the calculation of relative hydration free energies, relative binding free energies of a ligand-receptor system, and in silico alanine scanning of a peptide-protein complex. In all cases, good agreement with available experimental data was obtained. On medium sized protein-ligand systems and using a cluster of graphical processing units, the approach allows the calculation of relative free energy changes associated with a chemical modification of a binding partner within a few minutes of computer time and opens the possibility for systematic in silico studies.