Comparative ACE2 variation and primate COVID-19 risk

Amanda D. Melin; Mareike C. Janiak; Frank Marrone; Paramjit S. Arora; James P. Higham

The ACE2 receptors of all catarrhines have identical residues to humans across all 12 analyzed sites and are predicted to have similar binding affinity for SARS-CoV-2. Platyrrhines diverge from catarrhines at three of the twelve critical amino acid residues. Compared to catarrhine ACE2, the platyrrhines' ACE2 is predicted to bind SARS-CoV2 RBD with roughly 400-fold reduced affinity (ΔΔGbind=3.5 kcal/mol) (Table 1a ). In particular, the change at site 41 from Y to H found in . CC-BY-NC-ND 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.09.034967 doi: bioRxiv preprint monkeys in the Americas has the largest impact of any residue change examined (Table 1b) , which alone is predicted to lead to a 25-fold decrease in the binding affinity to SARS-CoV-2 ( Figure 2 ). This single mutation combined with additional substitutions, especially Q42E, found in platyrrhines is predicted to significantly reduce the likelihood of successful viral binding (Table 1b) . Of the other primates modeled, two of the three strepsirhines, and tarsiers, also have the H41 residue and furthermore have additional protein sequence differences leading to further decreases in predicted binding affinity. The predicted binding affinity of tarsier ACE2 is the most dissimilar to humans and this primate might be the least susceptible of the species we examine.