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Natural variants in SARS-CoV-2 S protein pinpoint structural and functional hotspots; implications for prophylaxis strategies

Suman Pokhrel, Benjamin R. Kraemer and Daria Mochly-Rosen
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 

The SARS-CoV-2 viral genome, including the gene for the Spike (S) protein that mediates host receptor binding and cellular entry, rapidly mutates as it spreads throughout the world. We analyzed a database of viral sequences isolated from patients, hosted by the Singapore Institute. As of November 11, we observed 4,517 unique variants within 1273 amino acid-long S protein and identified four regions with few mutations. These least variable regions are likely important functional and structural sites of the virus and therefore should be useful targets for prophylaxis. The conserved regions were the angiotensin converting enzyme (ACE2) receptor-binding domain (RBD), the linoleic acid (LA)-binding site, the trimer interface and a previously unidentified conserved region (F541-Y612), with no assigned function. All the other functional regions analyzed, including both furin proteolysis sites, the neuropolin-1 interaction site and the glycosylation sites, were highly variable, suggesting they are poor targets for prophylaxis. Furthermore, although the trimer interface is conserved, it is likely inaccessible for therapeutics. Focusing on the 26 amino acids in the RBD that lie within 4.5Å of ACE2, we further examined the potential impact of variants in these residues on the Spike-ACE2 affinity. Using Molecular Operating Environment software, only 7 of the 81 variants had increased calculated affinity by greater than 1kcal/mol. Whether any of the variants in this or other regions contribute to an increased infectivity (fitness) of the virus is not known. However, our analysis can guide the development of effective prophylactic agents to arrest the spread of the COVID-19 pandemic.