ABSTRACT
The Biochemistry Authentic Scientific Inquiry Laboratory (BASIL) has provided undergraduate biochemistry students with an inquiry‐based investigation into protein structure using a combination of computational and wet‐lab experimentation. Based on the skill set developed, BASIL faculty and students were invited to join a week‐long online boot camp hosted by Dr. Stephen Burley and colleagues at the Rutgers University Institute for Quantitative Biomedicine in July 2020. This session, entitled “The Summer of the Coronaverse,” saw teams of researchers analyzing genomic data to track emergence of different variants in SARS‐CoV‐2 Nsp5 (also known as main protease or Mpro) sequence. Teams used Mol*and FoldIt to model the protease and further analyze mutations of amino acids, categorizing them as conservative/nonconservative, and by location with the protein (surface/interior/boundary). Most mutations from existing SARS‐CoV‐2 strains were located distal to the enzyme’s active site and did not greatly effect the estimated protein stability relative to the parental sequence. As a result of the week spent investing these protease mutations, undergraduate students (a) learned to use online, accessible genomic and structure analysis tools, (b) experienced partnering with a large team of investigators, and (c) contributed to ongoing science, including publishing a manuscript on their results.
ABSTRACT
Understanding the molecular evolution of the SARS-CoV-2 virus as it continues to spread in communities around the globe is important for mitigation and future pandemic preparedness. Three-dimensional structures of SARS-CoV-2 proteins and those of other coronavirusess archived in the Protein Data Bank were used to analyze viral proteome evolution during the first 6 months of the COVID-19 pandemic. Analyses of spatial locations, chemical properties, and structural and energetic impacts of the observed amino acid changes in >48 000 viral isolates revealed how each one of 29 viral proteins have undergone amino acid changes. Catalytic residues in active sites and binding residues in protein-protein interfaces showed modest, but significant, numbers of substitutions, highlighting the mutational robustness of the viral proteome. Energetics calculations showed that the impact of substitutions on the thermodynamic stability of the proteome follows a universal bi-Gaussian distribution. Detailed results are presented for potential drug discovery targets and the four structural proteins that comprise the virion, highlighting substitutions with the potential to impact protein structure, enzyme activity, and protein-protein and protein-nucleic acid interfaces. Characterizing the evolution of the virus in three dimensions provides testable insights into viral protein function and should aid in structure-based drug discovery efforts as well as the prospective identification of amino acid substitutions with potential for drug resistance.