Using Dimensionality Reduction to Systematically Expand Conformational Sampling of Intrinsically Disordered Peptides
Using Dimensionality Reduction to Systematically Expand Conformational Sampling of Intrinsically Disordered Peptides
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DOI：
10.1021/acs.jctc.6b00503
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发表时间：
2016-10-01
影响因子：
5.5
通讯作者：
Peter, Christine
中科院分区：
文献类型：
--
作者：
Kukharenko, Oleksandra;Sawade, Kevin;Peter, Christine
提高我们表征生物学重要过程和绘制潜在自由能景观的能力的方法之一是指导MD模拟更快地探索分子构象相空间。具有大量亚稳极小值的浅自由能景观的内在无序系统在这方面提出了特别的挑战。通常不明确的构象状态的表征以及相空间勘探的收敛程度的评估都是有问题的。我们使用了一个多维标度样嵌入（草图）来描述本质上无序的蛋白a-突触核蛋白肽片段的能量可达的相空间区域。利用来自短暂初始模拟的草图坐标，我们指导了额外的MD模拟，以有效地扩展构象空间的采样。草图图投影非常适合于在大量数据中检测罕见但可能功能相关的事件、亚稳态中间产物和过渡状态。
One of the approaches to improve our ability to characterize biologically important processes and to map out an underlying free energy landscape is to direct MD simulations to explore molecular conformational phase space faster. Intrinsically disordered systems with shallow free energy landscapes of a huge number of metastable minima pose a particular challenge in this regard. Both characterization of the often ill-defined conformational states as well as the assessment of the degree of convergence of phase space exploration are problematic. We have used a multidimensional scaling-like embedding (sketch-map) to describe the energetically accessible regions of phase space for a peptide fragment of the intrinsically disordered protein a-synuclein. Using sketch-map coordinates from a short initial simulation, we guided additional MD simulations to efficiently expand sampling of the conformational space. The sketch-map projections are very well suited to detect rare but possibly functionally relevant events, metastable intermediates, and transition states in the vast amount of data.