Will molecular dynamics simulations of proteins ever reach equilibrium?
Will molecular dynamics simulations of proteins ever reach equilibrium?
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DOI：
10.1039/c2cp23961b
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发表时间：
2012-01-01
影响因子：
3.3
通讯作者：
Ryde, Ulf
中科院分区：
文献类型：
--
作者：
Genheden, Samuel;Ryde, Ulf
我们表明，即使采用 380-500 ns 长度的分子动力学 (MD) 模拟（不确定性为 12-89 kJ mol(-1)），使用二面体分布直方图、von Mises 方法或准调和分析计算的五种蛋白质和蛋白质-配体复合物的构象熵也不会收敛到任何有用的精度。为了解释这一点，我们建议使用一个简单的蛋白质模型，其中包含具有形成均匀分布的有效势垒的二面体，并表明对于这样的模型，熵随时间呈对数增加，直到对所有显着分布的二面体状态进行采样，这与模拟一致（在模拟期间，已访问了 52-70% 的可用二面体相空间）。对牛胰腺胰蛋白酶抑制剂的 1 ms 模拟轨迹分析也证实了这一点（模拟第一部分和第二部分之间的熵差异为 31 kJ mol(-1)）。严格来说，这意味着平衡蛋白质的 MD 模拟实际上是不可能的。我们讨论了蛋白质MD模拟缺乏严格平衡的影响，并表明用MM/GBSA方法（具有广义Born和表面积溶剂化的分子力学）估计的配体结合自由能在500 ns模拟期间变化3-15 kJ mol(-1)（较高的估计是由罕见的构象变化引起的），尽管它们涉及有问题但收敛良好的正态模式熵估计，而自由对于相同的模拟，通过自由能扰动估计的能量变化小于 0.6 kJ mol(-1)。
We show that conformational entropies calculated for five proteins and protein-ligand complexes with dihedral-distribution histogramming, the von Mises approach, or quasi-harmonic analysis do not converge to any useful precision even if molecular dynamics (MD) simulations of 380-500 ns length are employed (the uncertainty is 12-89 kJ mol(-1)). To explain this, we suggest a simple protein model involving dihedrals with effective barriers forming a uniform distribution and show that for such a model, the entropy increases logarithmically with time until all significantly populated dihedral states have been sampled, in agreement with the simulations (during the simulations, 52-70% of the available dihedral phase space has been visited). This is also confirmed by the analysis of the trajectories of a 1 ms simulation of bovine pancreatic trypsin inhibitor (31 kJ mol(-1) difference in the entropy between the first and second part of the simulation). Strictly speaking, this means that it is practically impossible to equilibrate MD simulations of proteins. We discuss the implications of such a lack of strict equilibration of protein MD simulations and show that ligand-binding free energies estimated with the MM/GBSA method (molecular mechanics with generalised Born and surface-area solvation) vary by 3-15 kJ mol(-1) during a 500 ns simulation (the higher estimate is caused by rare conformational changes), although they involve a questionable but well-converged normal-mode entropy estimate, whereas free energies estimated by free-energy perturbation vary by less than 0.6 kJ mol(-1) for the same simulation.