Martín-García Fernando, Papaleo Elena, Gomez-Puertas Paulino, Boomsma Wouter, Lindorff-Larsen Kresten
Molecular Modelling Group, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), C/Nicolás Cabrera 1, Cantoblanco, Madrid, Spain; Biomol-Informatics SL, Parque Científico de Madrid, Cantoblanco, Madrid, Spain.
Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
PLoS One. 2015 Mar 26;10(3):e0121114. doi: 10.1371/journal.pone.0121114. eCollection 2015.
The continued development and utility of molecular dynamics simulations requires improvements in both the physical models used (force fields) and in our ability to sample the Boltzmann distribution of these models. Recent developments in both areas have made available multi-microsecond simulations of two proteins, ubiquitin and Protein G, using a number of different force fields. Although these force fields mostly share a common mathematical form, they differ in their parameters and in the philosophy by which these were derived, and previous analyses showed varying levels of agreement with experimental NMR data. To complement the comparison to experiments, we have performed a structural analysis of and comparison between these simulations, thereby providing insight into the relationship between force-field parameterization, the resulting ensemble of conformations and the agreement with experiments. In particular, our results show that, at a coarse level, many of the motional properties are preserved across several, though not all, force fields. At a finer level of detail, however, there are distinct differences in both the structure and dynamics of the two proteins, which can, together with comparison with experimental data, help to select force fields for simulations of proteins. A noteworthy observation is that force fields that have been reparameterized and improved to provide a more accurate energetic description of the balance between helical and coil structures are difficult to distinguish from their "unbalanced" counterparts in these simulations. This observation implies that simulations of stable, folded proteins, even those reaching 10 microseconds in length, may provide relatively little information that can be used to modify torsion parameters to achieve an accurate balance between different secondary structural elements.
分子动力学模拟的持续发展和应用需要改进所使用的物理模型（力场）以及我们对这些模型的玻尔兹曼分布进行采样的能力。这两个领域的最新进展使得使用多种不同的力场对两种蛋白质（泛素和蛋白G）进行多微秒的模拟成为可能。尽管这些力场大多共享一种通用的数学形式，但它们在参数以及推导这些参数的理念上存在差异，并且先前的分析表明与实验核磁共振数据的吻合程度各不相同。为了补充与实验的比较，我们对这些模拟进行了结构分析和比较，从而深入了解力场参数化、所得构象集合以及与实验的吻合度之间的关系。特别是，我们的结果表明，在粗略层面上，许多运动特性在几种（尽管不是所有）力场中都得以保留。然而，在更精细的细节层面上，这两种蛋白质的结构和动力学存在明显差异，这与实验数据的比较一起，有助于为蛋白质模拟选择力场。一个值得注意的观察结果是，在这些模拟中，经过重新参数化和改进以更准确地描述螺旋结构和卷曲结构之间能量平衡的力场，很难与它们的“不平衡”对应物区分开来。这一观察结果意味着，对稳定的折叠蛋白质进行模拟，即使模拟时长达到10微秒，可能也只能提供相对较少的可用于修改扭转参数以在不同二级结构元件之间实现精确平衡的信息。
