Prediction of octanol-water partition coefficients for the SAMPL6-[Formula: see text] molecules using molecular dynamics simulations with OPLS-AA, AMBER and CHARMM force fields.
Prediction of octanol-water partition coefficients for the SAMPL6-[Formula: see text] molecules using molecular dynamics simulations with OPLS-AA, AMBER and CHARMM force fields.
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DOI：
10.1007/s10822-019-00267-z
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发表时间：
2020-05
影响因子：
3.5
通讯作者：
Beckstein O
中科院分区：
文献类型：
--
作者：
Fan S;Iorga BI;Beckstein O
在SAMPL6 LOG P盲预测挑战中，采用了分层化学自由能计算的全原子分子动力学模拟方法预测了11个小分子的辛醇-水分配系数logPOW，使用了四种不同的力场参数：带可转移电荷的标准OPLS-AA、带不可转移CM1a电荷的OPLS-AA、Amber/Gaff和CHARMM/CGenFF。通过比较密度随温度的变化与实验值的关系，验证了OPLS-AA、GAFF和CHARMM的辛醇参数。根据化合物在水和纯(“干”)辛醇或含27%水的“湿”辛醇中的溶剂化自由能计算分配系数。绝对溶剂化自由能用热力学积分(TI)和多态Bennett接受比(MBAR)计算，不相关的样品用Gromacs分子动力学程序进行5 ns加窗炼铝自由能微扰(FEP)计算。基于对前向轨迹和时间反向轨迹的分析，通过一种新的收敛度量来量化多组FEP模拟的平衡性。通过描述性统计指标，如数据集与实验值的均方根误差(RMSE)，评估了对数POW预测的准确性。丢弃每个5 ns窗口的前1 ns作为平衡阶段对GAFF数据有很大影响，它将RMSE提高了0.8个对数单位，而对其他数据集的影响较小或略有恶化。总体而言，CGenFF给出了RMSE 1.2对数单位的最佳预测，尽管只对8个分子进行了预测，因为目前针对Gromacs的CGenFF工作流程不会为某些含有卤素的化合物生成文件。在所有11种化合物中，Gaff给出的RMSE为1.5。使用水/辛醇混合溶剂的影响，对CGenFF和GAFF的准确度略有降低，对OPLS-AA的准确度略有提高。GAFF和OPLS-AA的结果显示了一个系统性错误，分子过于疏水，而CGenFF似乎更平衡，至少在这个小数据集上是这样。
All-atom molecular dynamics simulations with stratified alchemical free energy calculations were used to predict the octanol-water partition coefficient log Pow of eleven small molecules as part of the SAMPL6 log P blind prediction challenge using four different force field parametrizations: standard OPLS-AA with transferable charges, OPLS-AA with non-transferable CM1A charges, AMBER/GAFF, and CHARMM/CGenFF. Octanol parameters for OPLS-AA, GAFF and CHARMM were validated by comparing the density as a function of temperature to experimental values. The partition coefficients were calculated from the solvation free energy for the compounds in water and pure (“dry”) octanol or “wet” octanol with 27 mol % water dissolved. Absolute solvation free energies were computed by thermodynamic integration (TI) and the Multistate Bennett Acceptance Ratio (MBAR) with uncorrelated samples from data generated by an established protocol using 5-ns windowed alchemical free energy perturbation (FEP) calculations with the Gromacs molecular dynamics package. Equilibration of sets of FEP simulations was quantified by a new measure of convergence based on the analysis of forward and time-reversed trajectories. The accuracy of the log Pow predictions was assessed by descriptive statistical measures such as the root mean square error (RMSE) of the data set compared to the experimental values. Discarding the first 1 ns of each 5-ns window as an equilibration phase had a large effect on the GAFF data, where it improved the RMSE by up to 0.8 log units, while the effect for other data sets was smaller or marginally worsened the agreement. Overall, CGenFF gave the best prediction with RMSE 1.2 log units, although for only eight molecules because the current CGenFF workflow for Gromacs does not generate files for certain halogen-containing compounds. Over all eleven compounds, GAFF gave an RMSE of 1.5. The effect of using a mixed water/octanol solvent slightly decreased the accuracy for CGenFF and GAFF and slightly increased it for OPLS-AA. The GAFF and OPLS-AA results displayed a systematic error where molecules were too hydrophobic whereas CGenFF appeared to be more balanced, at least on this small data set.
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影响因子：
5.5
作者：
Hess, Berk;Kutzner, Carsten;Lindahl, Erik
通讯作者：
Lindahl, Erik
影响因子：
3.5
作者：
Klimovich, Pavel V.;Shirts, Michael R.;Mobley, David L.
通讯作者：
Mobley, David L.
影响因子：
14.9
作者：
Dodda LS;Cabeza de Vaca I;Tirado-Rives J;Jorgensen WL
通讯作者：
Jorgensen WL
影响因子：
3.5
作者：
Isik, Mehtap;Levorse, Dorothy;Chodera, John D.
通讯作者：
Chodera, John D.
DOI：
10.1016/s0166-1280(97)00237-6
发表时间：
1998-02-09
期刊：
THEOCHEM-JOURNAL OF MOLECULAR STRUCTURE
影响因子：
--
作者：
Jorgensen, WL;McDonald, NA
通讯作者：
McDonald, NA