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

El Ahdab, Dina; Lagardère, Louis; Inizan, Théo Jaffrelot; Célerse, Fréderic; Liu, Chengwen; Adjoua, Olivier; Jolly, Luc-Henri; Gresh, Nohad; Hobaika, Zeina; Ren, Pengyu; Maroun, Richard G.; Piquemal, Jean-Philip

[Image: see text] Following our previous work (Chem. Sci.2021, 12, 4889−490734168762), 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 μs) 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.