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 It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .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 8 Polymorphic variants mapped onto the ACE2 structure remarkably segregate into two distinct clusters at the ACE2/CoV-2 RBD interface (Figure 2 ). Enhancing variants cluster to the ACE2 surface most proximal to the receptor-binding ridge of CoV-2 RBD (Figure 3a) whereas the majority of the disrupting variants reside centrally on the two major ACE2 α-helices that substantially contribute to the buried surface area at the interface (Figure 4a) . Interestingly, the loop conformation in the receptor-binding ridge differs significantly in SARS-CoV-2 from that of SARS-CoV owing to the presence of bulky residues (V483 and E484) in the loop . This feature allows the CoV-2 loop to extend further towards ACE2 establishing more extensive contacts with the receptor. Hence, natural ACE2 variants in this region could be exploited by the CoV-2 loop, increasing susceptibility to viral infection. In contrast, most interactions that CoV-2 makes with the core of the ACE2 interface are centered on two α-helices and are mostly not unique to CoV-2. They seem to encompass critical binding hotspots, discussed below, and thus centrally located polymorphic variants are more likely to reduce viral recognition.