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

Another recurrent polymorphism in ACE2 maps to residue E35 and changes it to a lysine (Supplementary Table 1) . E35 establishes a critical polar contact with SARS-CoV-2 S-protein residue Q493, which is predicted to be attenuated in the presence of the positively charged lysine ( Figure 4B) . Interestingly, E35 is not conserved between SARS-CoV and SARS-CoV-2 S-proteins and hence we predict that it could offer selective protection from the SARS-CoV-2 infection in individuals carrying this variant. Other variants found in our analysis, including H34R ( Figure 4C ) and D38V, similarly result in a loss of interface polar contacts which are predicted to reduce ACE2 affinity for the viral RBD domain. Another interesting polymorphism at position 83 results in Y83H alteration. Residue Y83 underlies a hydrophobic pocket into which F486 from SARS-CoV-2 RBD is inserted (Supplementary Figure 5b) . This is another unique interaction involving ACE2 and the SARS-CoV-2 RBD F486 that is absent in SARS-CoV RBD where, the equivalent residue is a leucine . The polymorphism that replaces Y83 with a polar histidine will compromise the hydrophobic character of this unique pocket in addition to removing a polar contact with N487 ( Supplementary Figure 5b) , potentially offering selective protection from the SARS CoV-2 infections.