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

Area of Science:

• Biophysics
• Computational Chemistry
• Structural Biology

Background:

• SARS-CoV-2 Main Protease (Mpro) is a critical drug target.
• Understanding Mpro dimerization is key to developing inhibitors.
• Previous work established the importance of the Mpro dimerization interface.

Purpose of the Study:

• Investigate the structural dynamics of the SARS-CoV-2 Mpro dimerization interface.
• Elucidate the role of polarizable water molecules in allosteric communication.
• Compare allosteric connectivity using polarizable force fields (PFFs) versus non-PFFs.

Main Methods:

• Microsecond adaptive sampling molecular dynamics simulations (50 μs).
• Utilized the AMOEBA polarizable force field (PFF).
• Analyzed structural correlations between interface residues and the catalytic site.

Main Results:

• Identified a stable H-bond network at the dimerization interface, dependent on physiological pH.
• Confirmed a buried allosteric site within the Mpro structure.
• Observed significant differences in allosteric connectivity between PFFs and non-PFFs.
• Highlighted the crucial role of interfacial polarizable water molecules in mediating these differences.

Conclusions:

• Polarizable water molecules are integral to the Mpro dimerization interface's H-bond network.
• Water-interface many-body interactions drive interface volume fluctuations.
• These interactions mediate allosteric communication between the dimerization interface and the catalytic site.