Molecular Dynamics Simulations Indicate the SARS-CoV-2 Mpro Is Not a Viable Target for Small-Molecule Inhibitors Design

Maria Bzówka; Karolina Mitusinska; Agata Raczynska; Aleksandra Samol; Jack Tuszynski; Artur Góra

To investigate further possible mutations of SARS-CoV-2 Mpro, single nucleotide substitutions were introduced to the SARS-CoV-2 main protease gene. If a substitution of a single nucleotide caused translation to a different amino acid compared to the corresponding residue in the wild-type structure, an appropriate mutation was proposed with FoldX calculations. The most energetically favourable potential mutations were chosen based on a -1.5 kcal/mol threshold ( Figure 7A, Supplementary Table S2 ). Most of the energetically favourable potential mutations include amino acids that are solvent-exposed on the protein's surface, according to NetSurfP [35] results. These results show that in general, exposed amino acids are more likely to mutate.