Dynamic Docking Using Multicanonical Molecular Dynamics: Simulating Complex Formation at the Atomistic Level
Dynamic Docking Using Multicanonical Molecular Dynamics: Simulating Complex Formation at the Atomistic Level
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DOI：
10.1007/978-1-0716-1209-5_11
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发表时间：
2021-01-01
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通讯作者：
Kamiya, Narutoshi
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作者：
Bekker, Gert-Jan;Kamiya, Narutoshi
基于多正则分子动力学（McMD）的动态对接已被应用于预测几种蛋白质受体及其配体的天然结合构型。由于McMD的增强的采样能力，它可以穷尽地对结合和未结合的配体构型以及受体构象进行采样，从而实现对构象和构型空间的有效采样，这是使用规范MD模拟不可能实现的。由于McMD样品的配置空间很宽，需要进行广泛的分析，以研究由绑定和未绑定结构组成的不同的合奏。通过对多正则系综进行主成分分析，将加权后的系综投影到前两个主轴上，可以得到自由能景观（FEL）。进一步的分析产生位于FEL的局部最小值处的代表性结构，其中这些结构然后通过它们的自由能进行排名。在这一章中，我们描述了我们的动态对接方法，它成功地再现了小化合物，中型化合物和肽分子的天然结合构型。
Multicanonical molecular dynamics (McMD)-based dynamic docking has been applied to predict the native binding configurations for several protein receptors and their ligands. Due to the enhanced sampling capabilities of McMD, it can exhaustively sample bound and unbound ligand configurations, as well as receptor conformations, and thus enables efficient sampling of the conformational and configurational space, not possible using canonical MD simulations. As McMD samples a wide configurational space, extensive analysis is required to study the diverse ensemble consisting of bound and unbound structures. By projecting the reweighted ensemble onto the first two principal axes obtained via principal component analysis of the multicanonical ensemble, the free energy landscape (FEL) can be obtained. Further analysis produces representative structures positioned at the local minima of the FEL, where these structures are then ranked by their free energy. In this chapter, we describe our dynamic docking methodology, which has successfully reproduced the native binding configuration for small compounds, medium-sized compounds, and peptide molecules.