Computational investigation of the inhibition reaction on the free energy surface between SARS-Cov-2 Mpro and N3.

A detailed reaction mechanism of the inhibition process of substrate N3 for the main protease produced by the coronavirus has been clarified using the QM(CDRK)/MM approach. Minimum free energy path optimizations were performed using the free energy gradient and nudged elastic band methods. The free energy profile includes three reaction steps: one bond formation and two proton transfers. The highest free energy barrier was 16.3 kcal/mol for the final proton transfer from His40 to the N3 molecule. Free energy contribution analysis was performed to identify important residues consisting of Mpro. Arg40, Arg188, and Glu166 were identified around the active site to increase the reaction profile at the free energy barrier. [ABSTRACT FROM AUTHOR]