Shirts Michael R, Pande Vijay S
Department of Chemistry, Stanford University, Stanford, CA 94305-5080, USA.
J Chem Phys. 2005 Apr 1;122(13):134508. doi: 10.1063/1.1877132.
Quantitative free energy computation involves both using a model that is sufficiently faithful to the experimental system under study (accuracy) and establishing statistically meaningful measures of the uncertainties resulting from finite sampling (precision). In order to examine the accuracy of a range of common water models used for protein simulation for their solute/solvent properties, we calculate the free energy of hydration of 15 amino acid side chain analogs derived from the OPLS-AA parameter set with the TIP3P, TIP4P, SPC, SPC/E, TIP3P-MOD, and TIP4P-Ew water models. We achieve a high degree of statistical precision in our simulations, obtaining uncertainties for the free energy of hydration of 0.02-0.06 kcal/mol, equivalent to that obtained in experimental hydration free energy measurements of the same molecules. We find that TIP3P-MOD, a model designed to give improved free energy of hydration for methane, gives uniformly the closest match to experiment; we also find that the ability to accurately model pure water properties does not necessarily predict ability to predict solute/solvent behavior. We also evaluate the free energies of a number of novel modifications of TIP3P designed as a proof of concept that it is possible to obtain much better solute/solvent free energetic behavior without substantially negatively affecting pure water properties. We decrease the average error to zero while reducing the root mean square error below that of any of the published water models, with measured liquid water properties remaining almost constant with respect to our perturbations. This demonstrates there is still both room for improvement within current fixed-charge biomolecular force fields and significant parameter flexibility to make these improvements. Recent research in computational efficiency of free energy methods allows us to perform simulations on a local cluster that previously required large scale distributed computing, performing four times as much computational work in approximately a tenth of the computer time as a similar study a year ago.
定量自由能计算既涉及使用一个对所研究的实验系统足够忠实的模型（准确性），也涉及建立因有限采样而产生的不确定性的具有统计意义的度量（精度）。为了检验一系列用于蛋白质模拟的常见水模型在溶质/溶剂性质方面的准确性，我们使用TIP3P、TIP4P、SPC、SPC/E、TIP3P-MOD和TIP4P-Ew水模型计算了源自OPLS-AA参数集的15种氨基酸侧链类似物的水合自由能。我们在模拟中实现了高度的统计精度，获得的水合自由能不确定性为0.02 - 0.06千卡/摩尔，与相同分子的实验水合自由能测量结果相当。我们发现，旨在改善甲烷水合自由能的TIP3P-MOD模型与实验结果的匹配度始终是最接近的；我们还发现，准确模拟纯水性质的能力不一定能预测预测溶质/溶剂行为的能力。我们还评估了TIP3P的一些新颖修改版本的自由能，作为一种概念验证，即有可能在不大幅负面影响纯水性质的情况下获得更好的溶质/溶剂自由能行为。我们将平均误差降至零，同时将均方根误差降低到低于任何已发表水模型的水平，而测量的液态水性质相对于我们的扰动几乎保持不变。这表明当前的固定电荷生物分子力场仍有改进空间，并且有很大的参数灵活性来进行这些改进。自由能方法计算效率方面的最新研究使我们能够在本地集群上进行模拟，而这在以前需要大规模分布式计算，现在在大约十分之一的计算机时间内完成的计算工作量是一年前类似研究的四倍。
