Interfacial Water Many-Body Effects Drive Structural Dynamics and Allosteric Interactions in SARS-CoV-2 Main Protease Dimerization Interface
Interfacial Water Many-Body Effects Drive Structural Dynamics and Allosteric Interactions in SARS-CoV-2 Main Protease Dimerization Interface
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DOI：
10.1021/acs.jpclett.1c01460
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发表时间：
2021-07-01
影响因子：
5.7
通讯作者：
Piquemal, Jean-Philip
中科院分区：
文献类型：
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作者：
El Ahdab, Dina;Lagardere, Louis;Piquemal, Jean-Philip
根据我们之前的工作(化学。摘要/ abstract摘要：本文利用变形虫极化力场（PFF）进行微秒自适应采样分子动力学模拟（50 μ s），研究了SARS-CoV-2主蛋白酶二聚化界面（apo二聚体）的结构动力学。该界面由复杂的氢键网络构成，仅在生理ph下稳定。其残基和催化位点之间的结构相关性分析证实了埋藏变构位点的存在。然而，在pff和非pff之间观察到显着的变构连通性差异。界面极化水分子被证明是这种差异的核心，因为它们连接到全局界面氢键网络，并且能够适应它们的偶极矩（和动力学）以适应它们不同的局部物理化学微环境。水界面多体相互作用驱动界面体积波动，从而介导与催化腔的变构相互作用。
Following our previous work (Chem. Sci. 2021, 12, 4889-4907), we study the structural dynamics of the SARS-CoV-2 Main Protease dimerization interface (apo dimer) by means of microsecond adaptive sampling molecular dynamics simulations (50 mu s) using the AMOEBA polarizable force field (PFF). This interface is structured by a complex H-bond network that is stable only at physiological pH. Structural correlations analysis between its residues and the catalytic site confirms the presence of a buried allosteric site. However, noticeable differences in allosteric connectivity are observed between PFFs and non-PFFs. Interfacial polarizable water molecules are shown to appear at the heart of this discrepancy because they are connected to the global interface H-bond network and able to adapt their dipole moment (and dynamics) to their diverse local physicochemical microenvironments. The water-interface many-body interactions appear to drive the interface volume fluctuations and to therefore mediate the allosteric interactions with the catalytic cavity.