Water-triggered, irreversible conformational change of SARS-CoV-2 main protease on passing from the solid state to aqueous solution

Ansari, Narjes; Rizzi, Valerio; Carloni, Paolo; Parrinello, Michele

The main protease from SARS-CoV-2 is a homodimer. Yet, a recent 0.1 ms long molecular dynamics simulation shows that it readily undergoes a symmetry breaking event on passing from the solid state to the aqueous solution. As a result, the subunits present distinct conformations of the binding pocket. By analysing this long time simulation, here we uncover a previously unrecognised role of water molecules in triggering the transition. Interestingly, each subunit presents a different collection of long-lived water molecules. Enhanced sampling methods performed here, along with machine learning approaches, further establish that the transition to the asymmetric state is essentially irreversible.