Partial Atomic Charges and Their Impact on the Free Energy of Solvation
Partial Atomic Charges and Their Impact on the Free Energy of Solvation
复制标题
DOI：
10.1002/jcc.23117
复制
发表时间：
2013-01-30
影响因子：
3
通讯作者：
Laaksonen, Aatto
中科院分区：
文献类型：
--
作者：
Jambeck, Joakim P. M.;Mocci, Francesca;Laaksonen, Aatto
通过使用附加固定电荷力场的分子动力学模拟，计算了常见药物分子在水和正辛醇中的溶剂化自由能 (Delta G)。通过使用四种方法计算部分原子电荷来研究静电相互作用的影响，这四种方法都适合来自量子力学确定的静电势 (ESP) 的电荷。由于分子从气相转移到凝聚相时发生电子密度的重新分布，因此还研究了极化影响。通过计算放置在类似导体的连续体中的溶质的部分原子电荷，电荷被有效地极化以考虑极化效应。没有考虑偏振校正项或类似项，仅考虑部分原子电荷。结果表明，自由能对原子电荷的选择非常敏感，并且根据电荷计算方法，Delta G 可能相差几个 k(B)T。大多数方法中加入极化效应会使溶质过于亲水，而在真空电荷中则使溶质过于疏水。约束 ESP 方法与有效极化电荷一起在我们的测试集中表现良好，并且在应用于更大的分子集时也表现良好。水模型的效果也得到了强调，并表明得出的结论对于不同的三点模型都是有效的。如果考虑到两种环境的极化，也可以更好地描述水相和疏水相之间的分配，但结果同样对电荷计算方法敏感。总的来说，这里提出的结果表明，有效极化的电荷可以改善溶剂中类药物分子溶剂化的描述，并且部分原子电荷的选择对于确保分子模拟产生可靠的结果至关重要。 (C) 2012 年 Wiley 期刊公司 DOI：10.1002/jcc.23117
Free energies of solvation (Delta G) in water and n-octanol have been computed for common drug molecules by molecular dynamics simulations with an additive fixed-charge force field. The impact of the electrostatic interactions was investigated by computing the partial atomic charges with four methods that all fit the charges from the quantum mechanically determined electrostatic potential (ESP). Due to the redistribution of electron density that occurs when molecules are transferred from gas phase to condensed phase, the polarization impact was also investigated. By computing the partial atomic charges with the solutes placed in a conductor-like continuum, the charges were effectively polarized to take the polarization effects into account. No polarization correction term or similar was considered, only the partial atomic charges. Results show that free energies are very sensitive to the choice of atomic charges and that Delta G can differ by several k(B)T depending on the charge computing method. Inclusion of polarization effects makes the solutes too hydrophilic with most methods and in vacuo charges make the solutes too hydrophobic. The restrained-ESP methods together with effectively polarized charges perform well in our test set and also when applied to a larger set of molecules. The effect of water models is also highlighted and shows that the conclusions drawn are valid for different three-point models. Partitioning between an aqueous and a hydrophobic phase is also described better if the two environment's polarization is taken into account, but again the results are sensitive to the charge calculation method. Overall, the results presented here show that effectively polarized charges can improve the description of solvating a drug-like molecule in a solvent and that the choice of partial atomic charges is crucial to ensure that molecular simulations produce reliable results. (C) 2012 Wiley Periodicals, Inc. DOI: 10.1002/jcc.23117