Mobley David L, Bayly Christopher I, Cooper Matthew D, Shirts Michael R, Dill Ken A
Department of Chemistry, University of New Orleans, New Orleans, LA 70148.
J Chem Theory Comput. 2009 Feb 10;5(2):350-358. doi: 10.1021/ct800409d.
Using molecular dynamics free energy simulations with TIP3P explicit solvent, we compute the hydration free energies of 504 neutral small organic molecules and compare them to experiments. We find, first, good general agreement between the simulations and the experiments, with an RMS error of 1.24 kcal/mol over the whole set (i.e., about 2 kT) and a correlation coefficient of 0.89. Second, we use an automated procedure to identify systematic errors for some classes of compounds, and suggest some improvements to the force field. We find that alkyne hydration free energies are particularly poorly predicted due to problems with a Lennard-Jones well depth, and find that an alternate choice for this well depth largely rectifies the situation. Third, we study the non-polar component of hydration free energies - that is, the part that is not due to electrostatics. While we find that repulsive and attractive components of the non-polar part both scale roughly with surface area (or volume) of the solute, the total non-polar free energy does not scale with the solute surface area or volume, because it is a small difference between large components and is dominated by the deviations from the trend. While the methods used here are not new, this is a more extensive test than previous explicit solvent studies, and the size of the test set allows identification of systematic problems with force field parameters for particular classes of compounds. We believe that the computed free energies and components will be valuable to others in future development of force fields and solvation models.
使用带有TIP3P显式溶剂的分子动力学自由能模拟，我们计算了504种中性有机小分子的水合自由能，并将其与实验结果进行比较。首先，我们发现模拟结果与实验结果总体吻合良好，整个数据集的均方根误差为1.24千卡/摩尔（即约2kT），相关系数为0.89。其次，我们使用自动化程序识别某些化合物类别的系统误差，并对力场提出一些改进建议。我们发现，由于 Lennard-Jones 阱深存在问题，炔烃的水合自由能预测效果特别差，并发现该阱深的另一种选择在很大程度上纠正了这种情况。第三，我们研究了水合自由能的非极性成分——即不是由静电作用引起的部分。虽然我们发现非极性部分的排斥和吸引成分都大致与溶质的表面积（或体积）成比例，但总的非极性自由能并不与溶质表面积或体积成比例，因为它是大成分之间的微小差异，并且受趋势偏差的主导。虽然这里使用的方法并不新颖，但这是比以前的显式溶剂研究更广泛的测试，并且测试集的规模允许识别特定化合物类别的力场参数的系统问题。我们相信，计算得到的自由能和成分将对力场和溶剂化模型的未来发展中的其他人有价值。
