Differentially conserved amino acid positions may reflect differences in SARS-CoV-2 and SARS-CoV behaviour

Motivation: SARS-CoV-2 is a novel coronavirus currently causing a pandemic. Here, we per-formed a combined in-silico and cell culture comparison of SARS-CoV-2 and the closely related SARS-CoV.Results: Many amino acid positions are differentially conserved between SARS-CoV-2 and SARS-CoV, which reflects the discrepancies in virus behaviour, i.e. more effective human-to-human transmission of SARS-CoV-2 and higher mortality associated with SARS-CoV. Variations in the S protein (mediates virus entry) were associated with differences in its interaction with ACE2 (cellular S receptor) and sensitivity to TMPRSS2 (enables virus entry via S cleavage) inhi-bition. Anti-ACE2 antibodies more strongly inhibited SARS-CoV than SARS-CoV-2 infection, probably due to a stronger SARS-CoV-2 S-ACE2 affinity relative to SARS-CoV S. Moreover, SARS-CoV-2 and SARS-CoV displayed differences in cell tropism. Cellular ACE2 and TMPRSS2 levels did not indicate susceptibility to SARS-CoV-2. In conclusion, we identified genomic varia-tion between SARS-CoV-2 and SARS-CoV that may reflect the differences in their clinical and biological behaviour.