How Robust Are Protein Folding Simulations with Respect to Force Field Parameterization?
How Robust Are Protein Folding Simulations with Respect to Force Field Parameterization?
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DOI：
10.1016/j.bpj.2011.03.051
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发表时间：
2011-05-04
影响因子：
3.4
通讯作者：
Shaw, David E.
中科院分区：
文献类型：
--
作者：
Piana, Stefano;Lindorff-Larsen, Kresten;Shaw, David E.
分子动力学模拟有希望提供一个原子级的蛋白质折叠的描述，不能很容易地从实验中获得。在这里，我们研究在这种模拟中使用的分子力学力场可能会影响所观察到的折叠途径的程度。为此，我们使用四种不同的力场对绒毛帽的快速折叠变体进行了平衡模拟。在每个模拟中，我们观察到了大量的未折叠和折叠状态之间的转换，在所有四种情况下，折叠的速率和原生状态的结构都与实验吻合得很好。然而，我们发现，折叠机制和未折叠状态的性质基本上取决于力场的选择。因此，我们的结论是，虽然它是重要的，以匹配一个单一的，实验确定的结构和折叠速率，这并不能确保一个给定的模拟将提供一个独特的和正确的描述的完整的自由能表面和折叠的机制。
Molecular dynamics simulations hold the promise of providing an atomic-level description of protein folding that cannot easily be obtained from experiments. Here, we examine the extent to which the molecular mechanics force field used in such simulations might influence the observed folding pathways. To that end, we performed equilibrium simulations of a fast-folding variant of the villin headpiece using four different force fields. In each simulation, we observed a large number of transitions between the unfolded and folded states, and in all four cases, both the rate of folding and the structure of the native state were in good agreement with experiments. We found, however, that the folding mechanism and the properties of the unfolded state depend substantially on the choice of force field. We thus conclude that although it is important to match a single, experimentally determined structure and folding rate, this does not ensure that a given simulation will provide a unique and correct description of the full free-energy surface and the mechanism of folding.