Solvation free energies of amino acid side chain analogs for common molecular mechanics water models
Solvation free energies of amino acid side chain analogs for common molecular mechanics water models
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DOI：
10.1063/1.1877132
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发表时间：
2005-04-01
影响因子：
4.4
通讯作者：
Pande, VS
中科院分区：
文献类型：
--
作者：
Shirts, MR;Pande, VS
定量自由能计算涉及使用足够忠实于所研究的实验系统的模型（准确度）和建立有限采样（精度）导致的不确定性的统计学上有意义的测量。为了研究一系列常见的水模型用于蛋白质模拟其溶质/溶剂性质的准确性，我们计算了15个氨基酸侧链类似物的水化自由能，这些侧链类似物来自于具有TIP3P、TIP4P、SPC、SPC/E、TIP3P-MOD和TIP4P-Ew水模型的OPLS-AA参数集。我们实现了高度的统计精度在我们的模拟，获得的不确定性为0.02 - 0.06千卡/摩尔的水合自由能，相当于在实验中获得的相同分子的水合自由能测量。我们发现，TIP3P-MOD，一个模型的设计，以提高自由能的甲烷水化，给出一致的最接近的匹配实验，我们还发现，准确地模拟纯水的性能的能力并不一定预测能力预测溶质/溶剂的行为。我们还评估了自由能的一些新的修改TIP3P设计的概念证明，它是可能的，以获得更好的溶质/溶剂自由的高能行为，而不会产生实质性的负面影响纯水的性能。我们减少的平均误差为零，同时减少的均方根误差低于任何已公布的水模型，与测量的液态水的性质几乎保持不变，相对于我们的扰动。这表明，在当前的固定电荷生物分子力场中仍然存在改进的空间，并且在进行这些改进时具有显著的参数灵活性。自由能方法的计算效率的最新研究使我们能够在本地集群上进行模拟，以前需要大规模的分布式计算，在大约十分之一的计算机时间内执行四倍的计算工作。(C)2005年美国物理学会。
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. (C) 2005 American Institute of Physics.