Absolute Protein Binding Free Energy Simulations for Ligands with Multiple Poses, a Thermodynamic Path That Avoids Exhaustive Enumeration of the Poses
Absolute Protein Binding Free Energy Simulations for Ligands with Multiple Poses, a Thermodynamic Path That Avoids Exhaustive Enumeration of the Poses
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DOI：
10.1002/jcc.26078
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发表时间：
2019-10
影响因子：
3
通讯作者：
Y. Sakae;Bin W. Zhang;R. Levy;N. Deng
中科院分区：
文献类型：
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作者：
Y. Sakae;Bin W. Zhang;R. Levy;N. Deng
我们提出了一种自由能的计算方法，受体-配体结合，其中有多个结合位姿，避免穷举的姿态。对于具有多个结合位姿的系统，标准程序是枚举结合位姿的取向，将配体限制到每个取向，然后计算每个结合位姿的结合自由能。在这项研究中，我们修改了热力学循环的一部分，以采样更广泛的构象空间的配体的结合位点。这种修改导致更准确的自由能计算，而无需为每个结合姿势执行单独的自由能模拟。我们应用我们的修改简单的模型主-客体系统作为测试，其中只有两个结合位姿，通过使用一个单一的解耦方法（SDM）在隐式溶剂。结果表明，在不知道两种结合位姿的情况下，用该方法得到的结合自由能与通过显式枚举结合位姿得到的基准结果吻合较好.该方法也适用于其他的炼金术结合自由能计算方法，如显式溶剂中的双解耦方法。用改进的热力学路径计算了具有显式溶剂的蛋白质-配体体系的结合自由能，结果表明，沿着改进路径的自由能模拟结果与传统的DDM方法的结果吻合得很好，传统的DDM方法需要对显式溶剂中苯酚与T4溶菌酶结合的每一个结合位姿分别计算结合自由能.© 2019 Wiley Periodicals，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.