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

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.

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Frédéric Célerse, Théo Pierre Jaffrelot Inizan
2021
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https://infoscience.epfl.ch/record/287566?ln=fr

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Concepts associés (4)

Allosteric regulation

In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site. The site to which the effector binds is termed the allosteric site or regulatory site. Allosteric sites allow effectors to bind to the protein, often resulting in a conformational change and/or a change in protein dynamics. Effectors that enhance the protein's activity are referred to as allosteric activators, whereas those that decrease the protein's activity are called allosteric inhibitors.

Champ de force (chimie)

vignette|Un champ de force peut par exemple être utilisé afin de minimiser l'énergie d'étirement de cette molécule d'éthane. Dans le cadre de la mécanique moléculaire, un champ de force est un ensemble de potentiels et de paramètres permettant de décrire la structure de l'énergie potentielle d'un système de particules (typiquement, des atomes, mais non exclusivement). L'usage de l'expression champ de force en chimie et biologie numériques diffère ainsi de celui de la physique, où il indique en général un gradient négatif d'un potentiel scalaire.

Electric dipole moment

The electric dipole moment is a measure of the separation of positive and negative electrical charges within a system, that is, a measure of the system's overall polarity. The SI unit for electric dipole moment is the coulomb-meter (C⋅m). The debye (D) is another unit of measurement used in atomic physics and chemistry. Theoretically, an electric dipole is defined by the first-order term of the multipole expansion; it consists of two equal and opposite charges that are infinitesimally close together, although real dipoles have separated charge.