REVO: Resampling of ensembles by variation optimization
REVO: Resampling of ensembles by variation optimization
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DOI：
10.1063/1.5100521
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发表时间：
2019-06-28
影响因子：
4.4
通讯作者：
Dickson, Alex
中科院分区：
文献类型：
--
作者：
Donyapour, Nazanin;Roussey, Nicole M.;Dickson, Alex
传统的分子动力学模拟由于其高维性和粗糙的能量景观而无法对生物分子系统中的许多重要相互作用进行采样。为了观测这些系统中的稀有事件和计算跃迁率，必须加强采样。特别是，配体-蛋白质相互作用的研究需要蛋白质构象和过渡态的不同集合，并且对于许多系统，这发生在非常长的时间尺度上。以前的策略，如WExplore，可以用来确定这些类型的合奏阻碍了有关的问题，构象空间的区域。在这里，我们提出了一种新的，无区域的，增强的采样方法，是基于加权集成框架。在该方法中，在每个循环之后通过克隆和合并操作优化被称为“轨迹变化”的值。这种方法允许更一致的测量的可观察性和更广泛的采样，从而有效地探索以前未探索的构象。我们证明了该算法的性能与N维随机游走和解绑定的胰蛋白酶-苯甲脒系统。利用构象空间网络对该体系进行了分析，确定了苯甲脒的停留时间，并发现了胰蛋白酶-苯甲脒体系的一条新的解束缚路径，我们期望变分优化的系综重构将成为广泛探索自由能景观的一个有用的通用工具. (c)2019年作者。所有文章内容，除非另有说明，是根据知识共享署名（CC BY）许可证（http：//creativecommons.org/licenses/by/4.0/）。
Conventional molecular dynamics simulations are incapable of sampling many important interactions in biomolecular systems due to their high dimensionality and rough energy landscapes. To observe rare events and calculate transition rates in these systems, enhanced sampling is a necessity. In particular, the study of ligand-protein interactions necessitates a diverse ensemble of protein conformations and transition states, and for many systems, this occurs on prohibitively long time scales. Previous strategies such as WExplore that can be used to determine these types of ensembles are hindered by problems related to the regioning of conformational space. Here, we propose a novel, regionless, enhanced sampling method that is based on the weighted ensemble framework. In this method, a value referred to as "trajectory variation" is optimized after each cycle through cloning and merging operations. This method allows for a more consistent measurement of observables and broader sampling resulting in the efficient exploration of previously unexplored conformations. We demonstrate the performance of this algorithm with the N-dimensional random walk and the unbinding of the trypsin-benzamidine system. The system is analyzed using conformation space networks, the residence time of benzamidine is confirmed, and a new unbinding pathway for the trypsin-benzamidine system is found. We expect that resampling of ensembles by variation optimization will be a useful general tool to broadly explore free energy landscapes. (c) 2019 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).