In silico comparison of spike protein-ACE2 binding affinities across species; significance for the possible origin of the SARS-CoV-2 virus

Abstract

The devastating impact of the COVID-19 pandemic caused by SARS coronavirus 2 (SARS CoV 2) has raised important questions about viral origin, mechanisms of zoonotic transfer to humans, whether companion or commercial animals can act as reservoirs for infection, and why there are large variations in SARS-CoV-2 susceptibilities across animal species. Powerful in silico modelling methods can rapidly generate information on newly emerged pathogens to aid countermeasure development and predict future behaviours. Here we report an in silico structural homology modelling, protein-protein docking, and molecular dynamics simulation study of the key infection initiating interaction between the spike protein of SARS-Cov-2 and its target, angiotensin converting enzyme 2 (ACE2) from multiple species. Human ACE2 has the strongest binding interaction, significantly greater than for any species proposed as source of the virus. Binding to pangolin ACE2 was the second strongest, possibly due to the SARS-CoV-2 spike receptor binding domain (RBD) being identical to pangolin CoV spike RDB. Except for snake, pangolin and bat for which permissiveness has not been tested, all those species in the upper half of the affinity range (human, monkey, hamster, dog, ferret) have been shown to be at least moderately permissive to SARS-CoV-2 infection, supporting a correlation between binding affinity and permissiveness. Our data indicates that the earliest isolates of SARS-CoV-2 were surprisingly well adapted to human ACE2, potentially explaining its rapid transmission.