我们提出了一种受体-配体结合的自由能计算方法,它具有多个绑定姿势,避免了姿势的穷举枚举。对于具有多个绑定姿势的系统,标准程序是枚举绑定姿势的方向,将配体限制在每个方向,然后,计算每个结合姿势的结合自由能。在这项研究中,我们修改了热力循环的一部分,以便在结合位点采样配体的更宽构象空间。该修改导致更精确的自由能计算,而不对每个结合姿势执行单独的自由能模拟。我们将我们的修改应用于简单的模型主客系统作为测试,只有两个绑定姿势,通过在隐式溶剂中使用单解耦方法(SDM)。结果表明,在不知道两个结合姿势的情况下,从我们的方法获得的结合自由能与通过明确列举结合姿势获得的基准结果非常吻合。我们的方法适用于其他炼金术结合自由能计算方法,例如显式溶剂中的双解耦法(DDM)。我们使用修改的热力学路径对具有明确溶剂的蛋白质-配体系统进行了计算。沿着我们修改的路径的自由能模拟结果与常规DDM的结果非常吻合,这需要对苯酚在显式溶剂中与T4溶菌酶结合的示例的每个结合姿势进行单独的结合自由能计算。©2019Wiley期刊,Inc.
We propose a free energy calculation method for receptor-ligand binding, which have multiple binding poses that avoids exhaustive enumeration of the poses. For systems with multiple binding poses, the standard procedure is to enumerate orientations of the binding poses, restrain the ligand to each orientation, and then, calculate the binding free energies for each binding pose. In this study, we modify a part of the thermodynamic cycle in order to sample a broader conformational space of the ligand in the binding site. This modification leads to more accurate free energy calculation without performing separate free energy simulations for each binding pose. We applied our modification to simple model host-guest systems as a test, which have only two binding poses, by using a single decoupling method (SDM) in implicit solvent. The results showed that the binding free energies obtained from our method without knowing the two binding poses were in good agreement with the benchmark results obtained by explicit enumeration of the binding poses. Our method is applicable to other alchemical binding free energy calculation methods such as the double decoupling method (DDM) in explicit solvent. We performed a calculation for a protein-ligand system with explicit solvent using our modified thermodynamic path. The results of the free energy simulation along our modified path were in good agreement with the results of conventional DDM, which requires a separate binding free energy calculation for each of the binding poses of the example of phenol binding to T4 lysozyme in explicit solvent. © 2019 Wiley Periodicals, Inc.