Revealing Atomic-Level Mechanisms of Protein Allostery with Molecular Dynamics Simulations.
Revealing Atomic-Level Mechanisms of Protein Allostery with Molecular Dynamics Simulations.
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DOI：
10.1371/journal.pcbi.1004746
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发表时间：
2016-06
影响因子：
4.3
通讯作者：
Dror RO
中科院分区：
文献类型：
--
作者：
Hertig S;Latorraca NR;Dror RO
分子动力学 (MD) 模拟已成为研究蛋白质变构的一种强大而流行的方法，蛋白质变构是一种广泛存在的现象，即蛋白质上一个位点的刺激会影响蛋白质上另一个位点的特性。通过捕获蛋白质组成原子的运动，模拟可以发现变构结合位点并确定变构的机制基础。这些结果可以为合理药物设计和蛋白质工程等应用提供基础。在这里，我们介绍了使用分子动力学模拟研究蛋白质变构。我们强调设计模拟的重要性，其中包括对分子系统的适当扰动，例如配体的添加或去除或机械力的应用。我们还展示了变构的双向性质（涉及的两个位点以对称方式相互影响的事实）如何促进此类研究。通过一系列案例研究，我们说明了如何使用这些概念来揭示具有生物和制药意义的几种蛋白质和蛋白质复合物的变构结构基础。
Molecular dynamics (MD) simulations have become a powerful and popular method for the study of protein allostery, the widespread phenomenon in which a stimulus at one site on a protein influences the properties of another site on the protein. By capturing the motions of a protein’s constituent atoms, simulations can enable the discovery of allosteric binding sites and the determination of the mechanistic basis for allostery. These results can provide a foundation for applications including rational drug design and protein engineering. Here, we provide an introduction to the investigation of protein allostery using molecular dynamics simulation. We emphasize the importance of designing simulations that include appropriate perturbations to the molecular system, such as the addition or removal of ligands or the application of mechanical force. We also demonstrate how the bidirectional nature of allostery—the fact that the two sites involved influence one another in a symmetrical manner—can facilitate such investigations. Through a series of case studies, we illustrate how these concepts have been used to reveal the structural basis for allostery in several proteins and protein complexes of biological and pharmaceutical interest.