Molecular 'time-machines' to unravel key biological events for drug design
Molecular 'time-machines' to unravel key biological events for drug design
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DOI：
10.1002/wcms.1306
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发表时间：
2017-07-01
影响因子：
11.4
通讯作者：
Barakat, Khaled
中科院分区：
文献类型：
--
作者：
Ganesan, Aravindhan;Coote, Michelle L.;Barakat, Khaled
分子动力学（MD）已成为结构生物学和基于结构的药物设计（SBDD）的常规工具。 MD 对生物系统的结构和动力学提供了非凡的见解。凭借高性能超级计算机的当前能力，现在可以对数百万个原子和几纳秒时间尺度的系统进行MD模拟。然而，许多复杂的分子机制，包括配体结合/解结合和蛋白质折叠，通常发生在几微秒到毫秒的时间尺度上，这超出了标准MD模拟的实际限制。传统MD方法的此类问题可以通过新一代MD方法有效解决，例如增强采样MD方法和粗粒度MD（CG-MD）方案。前者采用偏差来引导模拟并揭示通常非常缓慢的生物事件，而后者将原子分组为相互作用珠，从而减小系统尺寸并促进更长的MD模拟，从而可以见证生物系统中的巨大构象变化。在这篇综述中，我们概述了许多此类先进的 MD 方法，并讨论了它们的应用如何为重要的生物过程，特别是与药物设计和发现相关的生物过程提供重要的见解。 (C) 2017 年 Wiley 期刊公司。
Molecular dynamics (MD) has become a routine tool in structural biology and structure-based drug design (SBDD). MD offers extraordinary insights into the structures and dynamics of biological systems. With the current capabilities of high-performance supercomputers, it is now possible to perform MD simulations of systems as large as millions of atoms and for several nanoseconds timescale. Nevertheless, many complicated molecular mechanisms, including ligand binding/unbinding and protein folding, usually take place on timescales of several microseconds to milliseconds, which are beyond the practical limits of standard MD simulations. Such issues with traditional MD approaches can be effectively tackled with new generation MD methods, such as enhanced sampling MD approaches and coarse-grained MD (CG-MD) scheme. The former employ a bias to steer the simulations and reveal biological events that are usually very slow, while the latter groups atoms as interaction beads, thereby reducing the system size and facilitating longer MD simulations that can witness large conformational changes in biological systems. In this review, we outline many of such advanced MD methods, and discuss how their applications are providing significant insights into important biological processes, particularly those relevant to drug design and discovery. (C) 2017 Wiley Periodicals, Inc.