Division of Physical Chemistry, Arrhenius Laboratory, Stockholm University, Stockholm, SE-10691, Sweden.
J Comput Chem. 2013 Jan 30;34(3):187-97. doi: 10.1002/jcc.23117. Epub 2012 Sep 20.
Free energies of solvation (ΔG) 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 ΔG 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.
通过分子动力学模拟和加和固定电荷力场，计算了常见药物分子在水中和正辛醇中的溶剂化自由能（ΔG）。通过计算四种方法的部分原子电荷来研究静电相互作用的影响，这四种方法都符合从量子力学确定的静电势（ESP）确定的电荷。由于分子从气相转移到凝聚相时电子密度的重新分布，还研究了极化的影响。通过将溶质置于导体连续体中计算部分原子电荷，可以有效地极化电荷以考虑极化效应。没有考虑极化校正项或类似项，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，ΔG 可能相差几个 k（B）T。包括极化效应会使大多数方法中的溶质过于亲水，而真空电荷会使溶质过于疏水。受约束的 ESP 方法与有效极化的电荷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。还强调了水模型的影响，表明得出的结论对于不同的三点模型是有效的。如果考虑到两个环境的极化，则水相和疏水性相之间的分配也可以更好地描述，但是结果仍然对电荷计算方法敏感。总体而言，这里呈现的结果表明，有效极化的电荷可以改善对药物样分子在溶剂中的溶剂化的描述，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。
