Mapping Conformational Dynamics of Proteins Using Torsional Dynamics Simulations
Mapping Conformational Dynamics of Proteins Using Torsional Dynamics Simulations
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DOI：
10.1016/j.bpj.2013.01.050
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发表时间：
2013-05-07
影响因子：
3.4
通讯作者：
Vaidehi, Nagarajan
中科院分区：
文献类型：
--
作者：
Gangupomu, Vamshi K.;Wagner, Jeffrey R.;Vaidehi, Nagarajan
全原子分子动力学模拟被广泛用于研究蛋白质构象的柔性。然而，需要增强的采样技术来模拟发生在毫秒时间尺度上的蛋白质动力学。在这项工作中，我们表明，扭转分子动力学模拟增强蛋白质构象采样进行构象搜索的低频扭转自由度。在这篇文章中，我们使用我们最近开发的扭转动力学方法称为广义牛顿-欧拉逆质量算子（GNEIMO）研究四种蛋白质的构象动力学。我们调查使用的GNEIMO方法在构象灵活的蛋白质fasciculin和钙调蛋白，以及灵活性较低的crambin和牛胰蛋白酶抑制剂的模拟。对于后两种蛋白质，GNEIMO模拟与隐式溶剂模型再现了平均蛋白质结构波动和样品构象类似的笛卡尔模拟与显式溶剂。GNEIMO与副本交换的研究fasciculin构象动力学的应用程序产生采样的两个这种蛋白质的实验建立的构象substates。GNEIMO模拟结果表明，钙调素的构象从Ca 2+结合态转变为无Ca 2+态。此外，GNEIMO方法产生了一个合奏的构象，满足约一半的短和长范围的interresidue距离从核磁共振结构的holo到apo的钙调蛋白转换。尽管无约束的全原子笛卡尔模拟未能对束状蛋白和钙调蛋白的亚态之间的跃迁进行采样，但GNEIMO模拟显示了这两个系统中的跃迁。捕获这些长时间尺度的构象动力学所需的相对较短的模拟时间表明，GNEIMO是一个很有前途的分子动力学技术，用于研究蛋白质中的结构域运动。
All-atom molecular dynamics simulations are widely used to study the flexibility of protein conformations. However, enhanced sampling techniques are required for simulating protein dynamics that occur on the millisecond timescale. In this work, we show that torsional molecular dynamics simulations enhance protein conformational sampling by performing conformational search in the low-frequency torsional degrees of freedom. In this article, we use our recently developed torsional-dynamics method called Generalized Newton-Euler Inverse Mass Operator (GNEIMO) to study the conformational dynamics of four proteins. We investigate the use of the GNEIMO method in simulations of the conformationally flexible proteins fasciculin and calmodulin, as well as the less flexible crambin and bovine pancreatic trypsin inhibitor. For the latter two proteins, the GNEIMO simulations with an implicit-solvent model reproduced the average protein structural fluctuations and sample conformations similar to those from Cartesian simulations with explicit solvent. The application of GNEIMO with replica exchange to the study of fasciculin conformational dynamics produced sampling of two of this protein's experimentally established conformational substates. Conformational transition of calmodulin from the Ca2+-bound to the Ca2+-free conformation occurred readily with GNEIMO simulations. Moreover, the GNEIMO method generated an ensemble of conformations that satisfy about half of both short- and long-range interresidue distances obtained from NMR structures of holo to apo transitions in calmodulin. Although unconstrained all-atom Cartesian simulations have failed to sample transitions between the substates of fasciculin and calmodulin, GNEIMO simulations show the transitions in both systems. The relatively short simulation times required to capture these long-timescale conformational dynamics indicate that GNEIMO is a promising molecular-dynamics technique for studying domain motion in proteins.