Relative Binding Free Energy Calculations for Ligands with Diverse Scaffolds with the Alchemical Transfer Method
Relative Binding Free Energy Calculations for Ligands with Diverse Scaffolds with the Alchemical Transfer Method
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DOI：
10.1021/acs.jcim.1c01129
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发表时间：
2022-01-06
影响因子：
5.6
通讯作者：
Gallicchio, Emilio
中科院分区：
文献类型：
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作者：
Azimi, Solmaz;Khuttan, Sheenam;Gallicchio, Emilio
我们提出了一个扩展的炼金术转移方法（ATM）的相对结合自由能的分子复合物适用于传统的，以及支架跳跃，炼金术转换的估计。该方法名为ATM-RBFE，在免费开源的OpenMM分子模拟包中实现，旨在提供一种比目前可用的更简单，更普遍适用的相对结合自由能计算路线。ATM-RBFE是基于健全的统计力学理论和一种新的坐标扰动计划，旨在交换一对配体的位置，使一个从本体溶剂转移到受体结合位点，而另一个同时在相反的方向移动。该计算是直接在一个单一的溶剂箱与传统的设置工具准备的系统，没有分裂的静电和非静电转换，没有成对的软核电位。ATM-RBFE在此针对SAMPL 8 GDCC主体-客体基准集的绝对结合自由能和针对包括雌激素受体ER α的复合物和甲基转移酶EZH 2的复合物的蛋白质-配体基准集进行验证。在每种情况下，该方法产生自洽和收敛的相对结合自由能估计与绝对结合自由能和参考文献值，以及实验测量。
We present an extension of the alchemical transfer method (ATM) for the estimation of relative binding free energies of molecular complexes applicable to conventional, as well as scaffold-hopping, alchemical transformations. Named ATM-RBFE, the method is implemented in the free and open-source OpenMM molecular simulation package and aims to provide a simpler and more generally applicable route to the calculation of relative binding free energies than what is currently available. ATM-RBFE is based on sound statistical mechanics theory and a novel coordinate perturbation scheme designed to swap the positions of a pair of ligands such that one is transferred from the bulk solvent to the receptor binding site while the other moves simultaneously in the opposite direction. The calculation is conducted directly in a single solvent box with a system prepared with conventional setup tools, without splitting of electrostatic and non-electrostatic transformations, and without pairwise soft-core potentials. ATM-RBFE is validated here against the absolute binding free energies of the SAMPL8 GDCC host-guest benchmark set and against protein-ligand benchmark sets that include complexes of the estrogen receptor ER alpha and those of the methyltransferase EZH2. In each case the method yields self-consistent and converged relative binding free energy estimates in agreement with absolute binding free energies and reference literature values, as well as experimental measurements.