The Dynamical Asymmetry in SARS-CoV2 Protease Reveals the Exchange Between Catalytic Activity and Stability in Homodimers.

The molecular approach to understanding the mechanisms of emerging diseases, like COVID-19, has largely accelerated the search for successful therapeutical strategies. In this work, we present an extensive molecular dynamics (MD) analysis of two forms of the SARS-CoV-2 main protease MPro. We analyzed the free form (apo) and compared the results with those coming from the (holo) form bound to the inhibitor Boceprevir, an FDA-approved drug repurposed for COVID-19 therapy. We applied Dynamic Cross Correlation (DCC) analysis to the MD simulations to trace the concerted motion patterns within the protein structure. Although symmetric, the homodimer in the bound form showed clearly asymmetric dynamical behavior. In particular, the presence of concerted motions was detected in the protomer where the expulsion of the substrate from the active site happened. Such behavior was not observed in the same time lapses in the apo form. These results highlight a sort of ‘symmetry breaking’, making a symmetric structure to display functional induced asymmetric behavior in response to a perturbation. This highly coordinated dynamics in response to an external cue confirms the character of ‘complex molecular machines’ of biopolymers.