Doudou Slimane, Burton Neil A, Henchman Richard H
School of Chemistry, The University of Manchester, Oxford Road, Manchester, M13 9PL, United Kingdom, and Manchester Interdisciplinary Biocentre, The University of Manchester, 131 Princess Street, Manchester M1 7DN, United Kingdom.
J Chem Theory Comput. 2009 Apr 14;5(4):909-18. doi: 10.1021/ct8002354. Epub 2009 Mar 10.
A practical approach that enables one to calculate the standard free energy of binding from a one-dimensional potential of mean force (PMF) is proposed. Umbrella sampling and the weighted histogram analysis method are used to generate a PMF along the reaction coordinate of binding. At each point, a restraint is applied orthogonal to the reaction coordinate to make possible the determination of the volume sampled by the ligand. The free energy of binding from an arbitrary unbound volume to the restrained bound form is calculated from the ratio of the PMF integrated over the bound region to that of the unbound. Adding the free energy changes from the standard-state volume to the unbound volume and from the restrained to the unrestrained bound state gives the standard free energy of binding. Exploration of the best choice of binding paths is also made. This approach is first demonstrated on a model binding system and then tested on the benzamidine-trypsin system for which reasonable agreement with experiment is found. A comparison is made with other methods to obtain the standard free energy of binding from the PMF.
提出了一种实用方法，可根据一维平均力势（PMF）计算结合的标准自由能。使用伞形采样和加权直方图分析方法沿结合反应坐标生成PMF。在每个点，施加与反应坐标正交的约束，以便能够确定配体采样的体积。从结合区域积分的PMF与未结合区域积分的PMF之比计算从任意未结合体积到受约束结合形式的结合自由能。将从标准状态体积到未结合体积以及从受约束到无约束结合状态的自由能变化相加，得到结合的标准自由能。还对结合路径的最佳选择进行了探索。该方法首先在模型结合系统上进行了演示，然后在苯甲脒 - 胰蛋白酶系统上进行了测试，发现与实验结果有合理的一致性。与从PMF获得结合标准自由能的其他方法进行了比较。
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