Human ACE2 receptor polymorphisms predict SARS-CoV-2 susceptibility

Eric W. Stawiski; Devan Diwanji; Kushal Suryamohan; Ravi Gupta; Frederic A. Fellouse; J. Fah Sathirapongsasuti; Jiang Liu; Ying-Ping Jiang; Aakrosh Ratan; Monika Mis; Devi Santhosh; Sneha Somasekar; Sangeetha Mohan; Sameer Phalke; Boney Kuriakose; Aju Antony; Jagath R. Junutula; Stephan C. Schuster; Natalia Jura; Somasekar Seshagiri

. 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 It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .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/10.1101/2020.04.07.024752 doi: bioRxiv preprint 9 Whereas the K26R variant stabilizes core ACE2 α-helical interactions, other naturally occurring polymorphic variants appear to locally destabilize or alter the Nterminus of ACE2 helix 1 (α1) conformation. The T27A mutant (Figure 3c ) removes side chain-backbone and backbone-backbone interactions between T27 and E30 likely increasing the local dynamics of helix α1. This would allow the N-terminus of α1 to bend slightly and accommodate the unique CoV-2 RBD receptor binding-ridge loop that more intimately contacts ACE2 compared to its SARS-CoV counterpart. Another predicted effect of the T27A variant is increased hydrophobicity at the interface, which could contribute to an increase in binding affinity. Similar destabilizing patterns can be inferred for S19P and E23K (Supplementary Table 4 ). Thus, the local α1 N-terminal helical flexibility along with N90 glycan destabilization may help accommodate the protrusive CoV-2 RBD receptor-binding ridge to form more extensive contacts with ACE2 and facilitate viral entry specifically for this virus.