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

To further understand the effect of the polymorphisms on receptor recognition by the SARS-CoV-2 RBD and to confirm our predictions, we structurally modeled the identified ACE2 variants using the recently published cryo-EM and crystal structures of ACE2/SARS-CoV-2 RBD complexes (Supplementary Table 4 ) Walls et al., 2020; Wrapp et al., 2020; Yan et al., 2020) . We combined our structural analysis predictions with data from the Procko study (Procko, 2020) and classified the polymorphisms into five categories. These included mutations that directly enhanced or disrupted the residues at the ACE2/S-protein binding interface or residues interacting with the N90-linked glycan. We term these mutations as "directly enhancing" or "directly disrupting". We also identified variants that were "indirectly enhancing" or "indirectly disrupting". These mutants were found to affect the residues that are at the ACE2/Sprotein binding interface but not in direct contact with the CoV-2 RBD residues. Lastly, we found several mutants that are located distal to the ACE2/S-protein binding site and do not mediate direct or indirect contacts with CoV-2 RBD. We classified these variants as "not relevant" in the context of our analysis. The enhancing variants were enriched in the mutagenesis screen (Procko, 2020) , while those ACE2 variants predicted to disrupt or weaken the ACE2/S-protein interactions were depleted (Procko, 2020) .