Phylogenetic and Ancestral Sequence Reconstruction of SARS-CoV-2 Reveals Latent Capacity to Bind Human ACE2 Receptor

SARS-CoV-2 is a unique event, having emerged suddenly as a highly infectious viral pathogen for human populations. Previous phylogenetic analyses show its closest known evolutionary relative to be a virus detected in bats (RaTG13), with a common assumption that SARS-CoV-2 evolved from a zoonotic ancestor via recent genetic changes (likely in the Spike protein receptor-binding domain or RBD) that enabled it to infect humans. We used detailed phylogenetic analysis, ancestral sequence reconstruction, and in situ molecular dynamics simulations to examine the Spike-RBD’s functional evolution, finding that the common ancestral virus with RaTG13, dating to no later than 2013, possessed high binding affinity to the human ACE2 receptor. This suggests that SARS-CoV-2 likely possessed a latent capacity to bind to human cellular targets (though this may not have been sufficient for successful infection) and emphasizes the importance of expanding efforts to catalog and monitor viruses circulating in both human and non-human populations. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00239-021-10034-0.