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Interfacial Water Many-body Effects Drive Structural Dynamics and Allosteric interactions in SARS-CoV-2 Main Protease Dimerization Interface

Abstract : 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 microseconds) using the AMOEBA polarizable force field (PFF). This interface is structured by a complex H-bond network that is only stable 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, since they are connected to the global interface H-bond network and able to adapt their dipole moment (and dynamics) to their diverse local physico-chemical micro-environments. The water-interface many-body interactions appear to drive the interface volume fluctuations and to therefore mediate the allosteric interactions with the catalytic cavity.
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https://hal.archives-ouvertes.fr/hal-03220156
Contributor : Jean-Philip Piquemal Connect in order to contact the contributor
Submitted on : Friday, May 7, 2021 - 8:57:12 AM
Last modification on : Thursday, November 10, 2022 - 4:34:34 AM

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Dina El Ahdab, Louis Lagardère, Theo Jaffrelot Inizan, Frédéric Célerse, Chengwen Liu, et al.. Interfacial Water Many-body Effects Drive Structural Dynamics and Allosteric interactions in SARS-CoV-2 Main Protease Dimerization Interface. Journal of Physical Chemistry Letters, 2021, 12, pp.6218-6226. ⟨10.1021/acs.jpclett.1c01460⟩. ⟨hal-03220156⟩

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