Calculating Partition Coefficients of Small Molecules in Octanol/Water and Cyclohexane/Water.
Calculating Partition Coefficients of Small Molecules in Octanol/Water and Cyclohexane/Water.
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DOI：
10.1021/acs.jctc.6b00449
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发表时间：
2016-08-09
影响因子：
5.5
通讯作者：
Mobley, David L.
中科院分区：
文献类型：
--
作者：
Bannan, Caitlin C.;Calabro, Gaetano;Kyu, Daisy Y.;Mobley, David L.
分配系数描述溶质如何在两种不混溶的溶剂之间分配。它们被用于药物设计中，作为溶质疏水性的量度和其膜渗透性的代表。我们在显式溶剂中使用分子动力学模拟从转移自由能计算分配系数。安装是由我们新的Solvation Toolkit完成的，它可以自动为许多流行的分子动力学软件包创建任何溶质和溶剂组合的输入文件。本文分别用广义琥珀力场（GAFF）和介电修正GAFF（GAFF-DC）计算了辛醇/水和环己烷/水的分配系数。使用过去类似的方法，我们发现水合自由能的均方根误差（RMSE）为6.3 kJ/mol，如果两种溶剂中的溶剂化自由能以相当的精度估计，则这相当于分配系数中约1.6 log单位的误差。在这里，我们发现两个力场的总RMSE约为1.2 log单位。GAFF和GAFF-DC的结果似乎表现出与GAFF和GAFF-DC计算的环己烷/水分配系数相反的方向的系统偏差。
Partition coefficients describe how a solute is distributed between two immiscible solvents. They are used in drug design as a measure of a solute’s hydrophobicity and a proxy for its membrane permeability. We calculate partition coefficients from transfer free energies using molecular dynamics simulations in explicit solvent. Setup is done by our new Solvation Toolkit which automates the process of creating input files for any combination of solutes and solvents for many popular molecular dynamics software packages. We calculate partition coefficients between octanol/water and cyclohexane/water with the Generalized AMBER Force Field (GAFF) and the Dielectric Corrected GAFF (GAFF-DC). With similar methods in the past we found a root-mean-squared error (RMSE) of 6.3 kJ/mol in hydration free energies which would correspond to an error of around 1.6 log units in partition coefficients if solvation free energies in both solvents were estimated with comparable accuracy. Here we find an overall RMSE of about 1.2 log units with both force fields. Results from GAFF and GAFF-DC seem to exhibit systematic biases in opposite directions with GAFF and GAFF-DC for calculated cyclohexane/water partition coefficients.
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