Department of Biochemistry, University of Washington, Seattle, Washington, USA.
Biophys J. 2010 Jul 21;99(2):647-55. doi: 10.1016/j.bpj.2010.04.062.
Protein dynamics on the atomic level and on the microsecond timescale has recently become accessible from both computation and experiment. To validate molecular dynamics (MD) at the submicrosecond timescale against experiment we present microsecond MD simulations in 10 different force-field configurations for two globular proteins, ubiquitin and the gb3 domain of protein G, for which extensive NMR data is available. We find that the reproduction of the measured NMR data strongly depends on the chosen force field and electrostatics treatment. Generally, particle-mesh Ewald outperforms cut-off and reaction-field approaches. A comparison to measured J-couplings across hydrogen bonds suggests that there is room for improvement in the force-field description of hydrogen bonds in most modern force fields. Our results show that with current force fields, simulations beyond hundreds of nanoseconds run an increased risk of undergoing transitions to nonnative conformational states or will persist within states of high free energy for too long, thus skewing the obtained population frequencies. Only for the AMBER99sb force field have such transitions not been observed. Thus, our results have significance for the interpretation of data obtained with long MD simulations, for the selection of force fields for MD studies and for force-field development. We hope that this comprehensive benchmark based on NMR data applied to many popular MD force fields will serve as a useful resource to the MD community. Finally, we find that for gb3, the force-field AMBER99sb reaches comparable accuracy in back-calculated residual dipolar couplings and J-couplings across hydrogen bonds to ensembles obtained by refinement against NMR data.
蛋白质在原子水平和微秒时间尺度上的动力学最近已经可以通过计算和实验来研究。为了在亚微秒时间尺度上验证分子动力学（MD）与实验的一致性，我们使用 10 种不同的力场配置对两种球状蛋白——泛素和蛋白 G 的 gb3 结构域进行了微秒级别的 MD 模拟，这些蛋白都有大量的 NMR 数据。我们发现，所测量的 NMR 数据的重现性强烈依赖于所选的力场和静电处理方式。通常，粒子网格 Ewald 方法优于截止和反应场方法。与测量的氢键 J 耦合的比较表明，在大多数现代力场中，氢键的力场描述还有改进的空间。我们的结果表明，目前的力场下，模拟时间超过数百纳秒会增加进入非天然构象状态的风险，或者会在高自由能状态下持续太长时间，从而扭曲获得的种群频率。只有 AMBER99sb 力场没有观察到这种转变。因此，我们的结果对于解释通过长 MD 模拟获得的数据、选择用于 MD 研究的力场以及力场开发具有重要意义。我们希望这个基于 NMR 数据的、针对许多流行的 MD 力场的综合基准能够成为 MD 社区的有用资源。最后，我们发现对于 gb3，力场 AMBER99sb 在反向计算的残余偶极耦合和氢键 J 耦合方面达到了与通过 NMR 数据精修得到的集合相当的精度。
