El Ahdab, DinaLagardere, LouisInizan, Theo JaffrelotCelerse, FredericLiu, ChengwenAdjoua, OlivierJolly, Luc-HenriGresh, NohadHobaika, ZeinaRen, PengyuMaroun, Richard G.Piquemal, Jean-Philip2021-07-312021-07-312021-07-312021-07-0810.1021/acs.jpclett.1c01460https://infoscience.epfl.ch/handle/20.500.14299/180329WOS:000672734200027Following 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.Chemistry, PhysicalNanoscience & NanotechnologyMaterials Science, MultidisciplinaryPhysics, Atomic, Molecular & ChemicalChemistryScience & Technology - Other TopicsMaterials SciencePhysicsmolecular-dynamicsrecognition. impactinhibitorsforcesimulationsproteinasenetworkssystemssitestext::journal::journal article::research article