Gustaf H. Carlson School of Chemistry and Biochemistry, Clark University , 950 Main Street, Worcester, Massachusetts 01610, United States.
Department of Mathematics and Computer Science, Clark University , 950 Main Street, Worcester, Massachusetts 01610, United States.
J Phys Chem B. 2017 Oct 26;121(42):9838-9847. doi: 10.1021/acs.jpcb.7b07528. Epub 2017 Oct 17.
Molecular dynamics simulations have become an important tool for the study of structures, dynamics, and functions of biomolecules. Time scales and force field accuracy are key factors for the reliability of these simulations. With the advancement of computational platforms and simulation technologies, all-atom simulations of proteins in explicitly represented aqueous solutions can reach as long as milliseconds. However, there are indications of minor force field flaws in literature. In this work we present our observations on force field accuracy under uncommon conditions. We performed molecular dynamics simulations of BBL refolding in aqueous solutions of acidic pH and high salt concentrations (up to 6 M) with the AMBER99SB-ILDN force field for a microsecond time scale. The reliability of the simulations relies on the accuracy of the physical models of protein, water, and ions. Our simulations show the same trend as experiments: higher salt concentration facilities refolding. However, we have observed the presence of β-sheet in the native helical region as well as α-helix and β-sheet in the native loop region. Some of the nonnative secondary structures are even more stable than native helices. Aside from the secondary structure issue under the uncommon conditions, we have found that the rigidity of glycine dihedral angles in the loop region leads to low root-mean-square deviations but large topological differences from the native structure. Whether this is due to a force field deficiency or not needs further investigations. Recently developed ion parameters exhibit evident liquid features even in the 6 M LiCl solution. However, cation-anion interactions in TIP3P water still seem too strong, leading to high fractions of contact ion pairs. We do not find any specific ion-binding motif, thus we conclude that the effect of salt is a nonspecific electrostatic screening in our simulations. Our observations on the AMBER force field performance under acidic conditions and high salt concentrations show that simulations under extreme conditions can provide informative tests of physical models.
分子动力学模拟已成为研究生物分子结构、动态和功能的重要工具。时间尺度和力场精度是这些模拟可靠性的关键因素。随着计算平台和模拟技术的进步，在明确表示的水溶液中对蛋白质进行全原子模拟可以达到长达毫秒的时间尺度。然而，文献中确实存在一些力场缺陷的迹象。在这项工作中，我们提出了在不常见条件下对力场精度的观察结果。我们使用 AMBER99SB-ILDN 力场在酸性 pH 和高盐浓度（高达 6 M）的水溶液中进行 BBL 重折叠的分子动力学模拟，时间尺度为微秒。模拟的可靠性依赖于蛋白质、水和离子的物理模型的准确性。我们的模拟显示与实验相同的趋势：较高的盐浓度有利于重折叠。然而，我们观察到在天然螺旋区域存在β-折叠，以及在天然环区域存在α-螺旋和β-折叠。一些非天然二级结构甚至比天然螺旋更稳定。除了不常见条件下的二级结构问题外，我们还发现环区域中甘氨酸二面角的刚性导致均方根偏差较低，但与天然结构的拓扑差异较大。这是否是由于力场缺陷引起的，还需要进一步研究。最近开发的离子参数即使在 6 M LiCl 溶液中也表现出明显的液体特征。然而，TIP3P 水中的阳离子-阴离子相互作用似乎仍然太强，导致接触离子对的比例很高。我们没有发现任何特定的离子结合模式，因此我们得出结论，在我们的模拟中，盐的作用是非特异性静电屏蔽。我们对 AMBER 力场在酸性条件和高盐浓度下的性能观察表明，极端条件下的模拟可以为物理模型提供有价值的测试。
