Parallel Tempering of Dark Matter from the Ebola Virus Proteome: Comparison of CHARMM36m and CHARMM22 Force Fields with Implicit Solvent,Journal of Chemical Information and Modeling

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Parallel Tempering of Dark Matter from the Ebola Virus Proteome: Comparison of CHARMM36m and CHARMM22 Force Fields with Implicit Solvent
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2017-12-15 00:00:00 , DOI: 10.1021/acs.jcim.7b00517
Mark A. Olson ₁

Affiliation

Intrinsically disordered proteins are characterized by their large manifold of thermally accessible conformations and their related statistical weights, making them an interesting target of simulation studies. To assess the development of a computational framework for modeling this distinct class of proteins, this work examines temperature-based replica-exchange simulations to generate a conformational ensemble of a 28-residue peptide from the Ebola virus protein VP35. Starting from a prefolded helix−β-turn–helix topology observed in a crystallographic assembly, the simulation strategy tested is the recently refined CHARMM36m force field combined with a generalized Born solvent model. A comparison of two replica-exchange methods is provided, where one is a traditional approach with a fixed set of temperatures and the other is an adaptive scheme in which the thermal windows are allowed to move in temperature space. The assessment is further extended to include a comparison with equivalent CHARMM22 simulation data sets. The analysis finds CHARMM36m to shift the minimum in the potential of mean force (PMF) to a lower fractional helicity compared with CHARMM22, while the latter showed greater conformational plasticity along the helix-forming reaction coordinate. Among the simulation models, only the adaptive tempering method with CHARMM36m found an ensemble of conformational heterogeneity consisting of transitions between α-helix−β-hairpin folds and unstructured states that produced a PMF of fractional fold propensity in qualitative agreement with circular dichroism experiments reporting a disordered peptide.

中文翻译：

埃博拉病毒蛋白质组中暗物质的平行回火：隐含溶剂的CHARMM36m和CHARMM22力场的比较

本质上无序的蛋白的特征在于其庞大的热可及构象及其相关的统计权重，使其成为模拟研究的有趣目标。为了评估用于建模这一独特类蛋白质的计算框架的开发，这项工作研究了基于温度的复制物交换模拟，以从埃博拉病毒蛋白VP35生成28个残基的肽的构象集合。从晶体学组件中观察到的预折叠螺旋-β-转-螺旋拓扑结构开始，测试的模拟策略是最近完善的CHARMM36m力场与广义的Born溶剂模型相结合。提供了两种副本交换方法的比较，其中一种是采用固定温度集的传统方法，另一种是自适应方案，其中允许热窗在温度空间中移动。评估进一步扩展，以包括与等效CHARMM22仿真数据集的比较。分析发现，与CHARMM22相比，CHARMM36m将平均力（PMF）的最小值移至较低的分数螺旋度，而后者沿螺旋形成反应坐标显示出更大的构象可塑性。在仿真模型中，

更新日期：2017-12-15

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