Accurately Modeling Nanosecond Protein Dynamics Requires at least Microseconds of Simulation
Accurately Modeling Nanosecond Protein Dynamics Requires at least Microseconds of Simulation
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DOI：
10.1002/jcc.23973
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发表时间：
2016-03-05
影响因子：
3
通讯作者：
Bowman, Gregory R.
中科院分区：
文献类型：
--
作者：
Bowman, Gregory R.
硬件和算法的进步极大地扩展了分子模拟的时间尺度。本文评估是否这样长的时间尺度模拟提高我们的能力来计算序参数，描述构象异质性的ps-ns时间尺度上，或者如果力场现在是一个限制因素。从实验的顺序参数进行了比较，从模拟范围从10 ns到100 μ s的长度在三种不同的方式计算的顺序参数。重要的是，采用自举法来评估每个模拟长度的结果的可变性。10-100 ns时间尺度模拟的结果是高度可变的，这可能解释了在研究不同蛋白质的已发表著作中模拟与实验之间的一致性水平的变化。幸运的是，微秒时间尺度模拟提高了计算的序参数的准确性和精度，至少只要使用全指数拟合或截断平均近似而不是常见的长期极限近似。这些长时间尺度模拟的精度提高了，可以对许多现代力场进行统计上合理的比较，例如Amber 03，Amber 99 sb-ILDN和Charmm 27。虽然这些力场之间存在一些变化，但对于足够长的模拟，它们通常给出非常相似的结果。需要进行如此多的模拟才能精确捕获ps-ns时间尺度过程，这一事实表明，对于较慢的过程，需要进行极其广泛的模拟。先进的采样技术可以帮助很大，但是，这样的方法将需要保持准确的动力学，如果他们是有价值的计算动力学性质，如序参数。(C)2015 Wiley Periodicals，Inc.
Advances in hardware and algorithms have greatly extended the timescales accessible to molecular simulation. This article assesses whether such long timescale simulations improve our ability to calculate order parameters that describe conformational heterogeneity on ps-ns timescales or if force fields are now a limiting factor. Order parameters from experiment are compared with order parameters calculated in three different ways from simulations ranging from 10 ns to 100 mu s in length. Importantly, bootstrapping is employed to assess the variability in results for each simulation length. The results of 10-100 ns timescale simulations are highly variable, possibly explaining the variation in levels of agreement between simulation and experiment in published works examining different proteins. Fortunately, microsecond timescale simulations improve both the accuracy and precision of calculated order parameters, at least so long as the full exponential fit or truncated average approximation is used instead of the common longtime limit approximation. The improved precision of these long timescale simulations allows a statistically sound comparison of a number of modern force fields, such as Amber03, Amber99sb-ILDN, and Charmm27. While there is some variation between these force fields, they generally give very similar results for sufficiently long simulations. The fact that so much simulation is required to precisely capture ps-ns timescale processes suggests that extremely extensive simulations are required for slower processes. Advanced sampling techniques could aid greatly, however, such methods will need to maintain accurate kinetics if they are to be of value for calculating dynamical properties like order parameters. (C) 2015 Wiley Periodicals, Inc.