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分子动力学模拟、相关网络和马尔可夫建模揭示的凝血酶变构反应中涉及的钠结合模式。

Na-binding modes involved in thrombin's allosteric response as revealed by molecular dynamics simulations, correlation networks and Markov modeling.

机构信息

Department of Physics, Wake Forest University, Winston Salem, NC, USA.

出版信息

Phys Chem Chem Phys. 2019 Feb 20;21(8):4320-4330. doi: 10.1039/c8cp07293k.

Abstract

The monovalent sodium ion (Na+) is a critical modulator of thrombin. However, the mechanism of thrombin's activation by Na+ has been widely debated for more than twenty years. Details of the linkage between thrombin and Na+ remain vague due to limited temporal and spatial resolution in experiments. In this work, we combine microsecond scale atomic-detailed molecular dynamics simulations with correlation network analyses and hidden Markov modeling to probe the detailed thermodynamic and kinetic picture of Na+-binding events and their resulting allosteric responses in thrombin. We reveal that ASP189 and ALA190 comprise a stable Na+-binding site (referred as "inner" Na+-binding site) along with the previously known one (referred as "outer" Na+-binding site). The corresponding newly identified Na+-binding mode introduces significant allosteric responses in thrombin's regulatory regions by stabilizing selected torsion angles of residues responsive to Na+-binding. Our Markov model indicates that the bound Na+ prefers to transfer between the two Na+-binding sites when an unbinding event takes place. These results suggest a testable hypothesis of a substrate-driven Na+ migration (ΔG ∼ 1.7 kcal mol-1) from the "inner" Na+-binding site to the "outer" one during thrombin's catalytic activities. The binding of a Na+ ion at the "inner" Na+-binding site should be inferred as a prerequisite for thrombin's efficient recognition to the substrate, which opens a new angle for our understanding of Na+-binding's allosteric activation on thrombin and sheds light on detailed processes in thrombin's activation.

摘要

单价钠离子(Na+)是凝血酶的关键调节剂。然而,超过二十年来,凝血酶被 Na+激活的机制一直存在广泛争议。由于实验中时间和空间分辨率有限,凝血酶与 Na+之间的联系细节仍然模糊不清。在这项工作中,我们结合微秒级原子细节分子动力学模拟与相关网络分析和隐马尔可夫建模,来探测 Na+结合事件及其在凝血酶中产生的变构响应的详细热力学和动力学图景。我们揭示了 ASP189 和 ALA190 组成了一个稳定的 Na+结合位点(称为“内”Na+结合位点),以及之前已知的一个(称为“外”Na+结合位点)。相应的新鉴定的 Na+结合模式通过稳定对 Na+结合有响应的残基的选定扭转角,在凝血酶的调节区域中引入了显著的变构响应。我们的马尔可夫模型表明,当发生结合解离事件时,结合的 Na+更喜欢在两个 Na+结合位点之间转移。这些结果提出了一个可测试的假设,即在凝血酶的催化活性过程中,Na+从“内”Na+结合位点向“外”Na+结合位点的底物驱动的 Na+迁移(ΔG∼1.7 kcal mol-1)。Na+离子在“内”Na+结合位点的结合应该被推断为凝血酶对底物的有效识别的前提条件,这为我们理解 Na+结合对凝血酶的变构激活开辟了新视角,并为凝血酶激活的详细过程提供了线索。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9293/6993936/136df9e92dcc/nihms-1064235-f0001.jpg

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