Maturation of the SARS-CoV-2 virus is regulated by dimerization of its main protease

SARS-CoV-2 main protease (M^pro) involved in COVID-19 is required for maturation of the virus and infection of host cells. The key question is how to block the activity of M^pro. By combining atomistic simulations with machine learning, we found that the enzyme regulates its own activity by a collective allosteric mechanism that involves dimerization and binding of a single substrate. At the core of the collective mechanism is the coupling between the catalytic site residues, H41 and C145, which direct the activity of M^pro dimer, and two salt bridges formed between R4 and E290 at the dimer interface. If these salt bridges are mutated, the activity of M^pro is blocked. The results suggest that dimerization of main proteases is a general mechanism to foster coronavirus proliferation, and propose a robust drug-based strategy that does not depend on the frequently mutating spike proteins at the viral envelope used to develop vaccines.