Department of Chemistry, Lehman College, The City University of New York, 250 Bedford Park Boulevard West, Bronx, New York 10468, United States.
Ph.D. Program in Biochemistry, The Graduate Center of The City University of New York, New York, New York 10016, United States.
J Chem Theory Comput. 2021 May 11;17(5):2714-2724. doi: 10.1021/acs.jctc.0c01185. Epub 2021 Apr 8.
Grid Inhomogeneous Solvation Theory (GIST) maps out solvation thermodynamic properties on a fine meshed grid and provides a statistical mechanical formalism for thermodynamic end-state calculations. However, differences in how long-range nonbonded interactions are calculated in molecular dynamics engines and in the current implementation of GIST have prevented precise comparisons between free energies estimated using GIST and those from other free energy methods such as thermodynamic integration (TI). Here, we address this by presenting PME-GIST, a formalism by which particle mesh Ewald (PME)-based electrostatic energies and long-range Lennard-Jones (LJ) energies are decomposed and assigned to individual atoms and the corresponding voxels they occupy in a manner consistent with the GIST approach. PME-GIST yields potential energy calculations that are precisely consistent with modern simulation engines and performs these calculations at a dramatically faster speed than prior implementations. Here, we apply PME-GIST end-state analyses to 32 small molecules whose solvation free energies are close to evenly distributed from 2 kcal/mol to -17 kcal/mol and obtain solvation energies consistent with TI calculations ( = 0.99, mean unsigned difference 0.8 kcal/mol). We also estimate the entropy contribution from the second and higher order entropy terms that are truncated in GIST by the differences between entropies calculated in TI and GIST. With a simple correction for the high order entropy terms, PME-GIST obtains solvation free energies that are highly consistent with TI calculations ( = 0.99, mean unsigned difference = 0.4 kcal/mol) and experimental results ( = 0.88, mean unsigned difference = 1.4 kcal/mol). The precision of PME-GIST also enables us to show that the solvation free energy of small hydrophobic and hydrophilic molecules can be largely understood based on perturbations of the solvent in a region extending a few solvation shells from the solute. We have integrated PME-GIST into the open-source molecular dynamics analysis software CPPTRAJ.
网格不均匀溶剂化理论 (GIST) 在细网格上绘制溶剂化热力学性质，并提供热力学终态计算的统计力学形式。然而，分子动力学引擎中长程非键相互作用的计算方式与 GIST 当前实现之间的差异，使得使用 GIST 估计的自由能与其他自由能方法（如热力学积分 (TI)）之间的精确比较变得困难。在这里，我们通过提出 PME-GIST 来解决这个问题，这是一种形式，其中基于粒子网格 Ewald (PME) 的静电能和长程 Lennard-Jones (LJ) 能被分解并分配给单个原子及其在 GIST 方法中一致的相应体素。PME-GIST 产生与现代模拟引擎精确一致的势能计算，并以比以前的实现快得多的速度执行这些计算。在这里，我们将 PME-GIST 末端状态分析应用于 32 种小分子，它们的溶剂化自由能接近均匀分布在 2 kcal/mol 到 -17 kcal/mol 之间，并获得与 TI 计算一致的溶剂化能（ = 0.99，平均无偏差 0.8 kcal/mol）。我们还估计了 GIST 中截断的二阶和更高阶熵项对熵的贡献，方法是比较 TI 和 GIST 计算的熵。通过对高阶熵项进行简单修正，PME-GIST 获得的溶剂化自由能与 TI 计算（ = 0.99，平均无偏差 = 0.4 kcal/mol）和实验结果（ = 0.88，平均无偏差 = 1.4 kcal/mol）高度一致。PME-GIST 的精度还使我们能够表明，基于溶质几个溶剂化壳层范围内溶剂的扰动，可以在很大程度上理解小疏水分子和亲水分子的溶剂化自由能。我们已经将 PME-GIST 集成到开源分子动力学分析软件 CPPTRAJ 中。
