Computational analysis of dynamic allostery and control in the SARS-CoV-2 main protease.
Computational analysis of dynamic allostery and control in the SARS-CoV-2 main protease.
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DOI：
10.1098/rsif.2020.0591
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
McLeish TCB
中科院分区：
文献类型：
--
作者：
Dubanevics I;McLeish TCB
由新型冠状病毒SARS-CoV-2引起的COVID-19大流行在撰写本文时没有公开可用的疫苗或抗病毒药物。一个有吸引力的冠状病毒药物靶标是主要蛋白酶（Mpro，也称为3CLpro），因为它在病毒周期中起着至关重要的作用。大量的工作集中在寻找结合和阻断主要蛋白酶活性位点的抑制剂上，但很少有人致力于解决潜在的非竞争性抑制，靶向活性位点以外的区域，部分原因是对这种变构控制的基本生物物理学仍然知之甚少。在这项工作中，我们构建了一个弹性网络模型（ENM）的SARS-CoV-2 Mpro同源二聚体蛋白质，并分析其动力学和热力学。我们发现了一个丰富的和异质的动力学结构，包括变构相关的运动之间的同源二聚体蛋白酶的活性位点。详尽的1-点和2-点突变扫描的ENM和它们的波动自由能的影响确认以前实验确定的生物活性残留物，但也提出了几个新的候选区域，远离活性位点，但控制蛋白酶功能。我们的研究结果表明，新的动态驱动的控制区域作为可能的候选人的非竞争性抑制结合位点的蛋白酶，这可能有助于目前的片段为基础的结合屏幕的发展。这些结果也为蛋白质波动变构及其动力学结构的生物物理研究提供了新的视角。
The COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2 has no publicly available vaccine or antiviral drugs at the time of writing. An attractive coronavirus drug target is the main protease (Mpro, also known as 3CLpro) because of its vital role in the viral cycle. A significant body of work has been focused on finding inhibitors which bind and block the active site of the main protease, but little has been done to address potential non-competitive inhibition, targeting regions other than the active site, partly because the fundamental biophysics of such allosteric control is still poorly understood. In this work, we construct an elastic network model (ENM) of the SARS-CoV-2 Mpro homodimer protein and analyse its dynamics and thermodynamics. We found a rich and heterogeneous dynamical structure, including allosterically correlated motions between the homodimeric protease's active sites. Exhaustive 1-point and 2-point mutation scans of the ENM and their effect on fluctuation free energies confirm previously experimentally identified bioactive residues, but also suggest several new candidate regions that are distant from the active site, yet control the protease function. Our results suggest new dynamically driven control regions as possible candidates for non-competitive inhibiting binding sites in the protease, which may assist the development of current fragment-based binding screens. The results also provide new insights into the active biophysical research field of protein fluctuation allostery and its underpinning dynamical structure.
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影响因子：
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影响因子：
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作者：
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DOI：
10.1080/07391102.2020.1758791
发表时间：
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发表时间：
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期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
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作者：
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影响因子：
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作者：
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