Impactful Mutations in Mpro of the SARS-CoV-2 Proteome

We explore how amino acid mutations affect the stability of the 306 residue main protease of the COVID-19 proteome. We employ two computational approaches, Site Directed Mutagenesis (SDM) and short runs of Molecular Dynamics. We focus our attention on residues 25-32 that make up a beta sheet of a canonical beta barrel close to an active site which includes Histidine 41. We considered this region a good candidate for mutations because such a large perturbation of a highly structured region close to the active site may prove to be highly detrimental to the protein's stability and may affect catalytic efficiency. Understanding how amino acid mutations affect the stability of the protein can inform efforts to develop pharmacological interventions. We mutated the 8 residues in silico to all other possible amino acids, and analyzed the resulting 152 mutants. Both computational methods predict that only a few specific mutations to some of the 8 residues have a major effect on the structural stability of the protein.