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

By far the most frequent variant identified in our data, K26R (~0.4% allele frequency), is predicted to enhance ACE2 affinity for SARS-CoV-2. Structural analysis of this polymorphism shows that K26 establishes polar contacts with the first mannose moiety of the ACE2 N90-linked glycan and likely stabilizes the position of the glycan relative to ACE2 (Figure 3b ). As discussed above, the N90-linked glycan emerges as an important determinant of CoV-2 infectivity and may diminish ACE2 affinity for the RBD possibly through steric hindrance imposed by branching of the sugar modifications (Demogines et al., 2012) . We predict that K26R would abrogate stabilizing polar contacts with N90, impairing coordination of the glycan (Figure 3b ) and lead to an increase in the affinity of the virus to the ACE2 receptor. At the same time, R26 is now primed to establish backbone and side chain interactions with ACE2 D30 which then is poised to build a salt-bridge with CoV-2 RBD K417 (Figure 3b) . The net effect of R26 polymorphism would then be the stabilization of core α-helices that increases ACE2 binding affinity to CoV-2 RBD at the cost of glycan rigidity. As discussed above, another enhancing variant, T92I, is structurally predicted to lead to similar effects by directly eliminating the N90-linked glycan.