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.