Biophysical characterization of the SARS-CoV2 spike protein binding with the ACE2 receptor explains increased COVID-19 pathogenesis

Ratul Chowdhury; Costas D Maranas

Recent reports indicate that domestic animals (dogs and cats) can also contract COVID-19 6 from humans, however, animal-to-human transmission has not been reported. Similar to SARS-CoV-1 7 , it has been reported that felines are more susceptible to SARS-CoV-2 followed by canines 8 whereas chickens and ferrets are less susceptible 8 . As seen in Figure 7 the calculated Rosetta binding energies largely, but not entirely, follow the trends expected from their respective sequence identities with the human ACE2 (see supplementary information for full sequence alignment). In all cases, the Rosetta binding energies for all animal ACE2s were at most 78.3% of the one calculated with hACE2. We found that feline ACE2 had the closest (78.3% of hACE2-spike RBD) Rosetta binding energy with the spike (see Figure 8 for contrasting spike interactions between feline and canine ACE2). Bovine ACE2 even though it is closer to human (95.2% seq. id. vs. 92.9% for feline) had the lowest Rosetta binding energy (72.2%) among all tested animal ACE2s except for chicken. Canine and equine ACE2 were similar and in between feline and bovine in terms of their Rosetta binding energies. Chicken ACE2 is by far the most distant from human and also was predicted to be the least effective in binding the viral spike protein RBD. These findings seem to be in broad agreement with the literature reports on the relative animal susceptibility to COVID-19. shows an electrostatic link between Tyr442 and His34, while canine ACE2 establishes a self-stabilizing salt bridge between Lys30 and Gly34, thus disallowing spike Tyr442 from establishing an electrostatic contact with any nearby ACE2 residue.