Detecting Allosteric Networks Using Molecular Dynamics Simulation.
Detecting Allosteric Networks Using Molecular Dynamics Simulation.
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DOI：
10.1016/bs.mie.2016.05.027
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发表时间：
2016
影响因子：
--
通讯作者：
Wereszczynski J
中科院分区：
文献类型：
--
作者：
Bowerman S;Wereszczynski J
变构网络允许酶在很远的距离上传递信息并调节其催化活性。原则上，分子动力学（MD）模拟可以用来揭示这种现象背后的机制;在实践中，很难从MD轨迹中辨别变构信号。在这里，我们描述了如何MD模拟可以分析，以揭示相关的运动和变构网络，并提供了一个例子，他们使用的凝血酶凝血酶。讨论了从原子涨落和互信息计算残基对相关性的方法，这些方法可以与接触信息相结合来识别变构网络并动态地将系统聚类为高度相关的社区。在凝血酶的情况下，这些方法表明，拮抗剂水蛭素的结合显着改变了酶的相关景观通过一系列的外位点I和催化核心之间的途径。结果表明，水蛭素结合削减动态多样性，并强制执行更严格的场地的影响，从而减少凝血酶的可及性，以其他分子。
Allosteric networks allow enzymes to transmit information and regulate their catalytic activities over vast distances. In principle, molecular dynamics (MD) simulations can be used to reveal the mechanisms that underlie this phenomenon; in practice, it can be difficult to discern allosteric signals from MD trajectories. Here, we describe how MD simulations can be analyzed to reveal correlated motions and allosteric networks, and provide an example of their use on the coagulation enzyme thrombin. Methods are discussed for calculating residue-pair correlations from atomic fluctuations and mutual information, which can be combined with contact information to identify allosteric networks and to dynamically cluster a system into highly correlated communities. In the case of thrombin, these methods show that binding of the antagonist hirugen significantly alters the enzyme’s correlation landscape through a series of pathways between Exosite I and the catalytic core. Results suggest that hirugen binding curtails dynamic diversity and enforces stricter venues of influence, thus reducing the accessibility of thrombin to other molecules.