The coronavirus 3C-like main protease (MPro) - an important target of COVID-19 drugs - has approximately half of the activity and an asymmetric dimer structure at certain pH, suggesting that only one catalytic site is active at a time. However, the mechanism that leads to this asymmetry is unknown. Prior to the COVID-19 pandemic, previous modeling studies that investigated the asymmetry of MPro were only about 148 ns long. In the last few years, several groups have produced much longer simulations of MPro and released them to the public for detailed analysis. Here, we analyze a 100 microsecond simulation produced by D.E. Shaw Research (DESRES) and a series of trajectories with an aggregate time of 2.9-millisecond produced by Folding@Home to investigate the mechanism by which asymmetry emerges. The D.E. Shaw simulation reveals a domino chain initiated by the breaking of the salt-bridge Arg4*-Glu290 that propagates to alternate conformations of the catalytic sites. Markov state model analysis of the Folding@Home simulations reveal that transitions between active and inactive conformations in two subunits are reversible and that one subunit is preferentially in an active conformation.

Symmetry-breaking mechanisms of the SARS-CoV-2 main protease

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