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

ACE2 polymorphic variants predicted to confer protection against the virus (Supplementary Tables 2 and 4) present compelling mechanistic explanations for how they may offer protection against the virus. The vast majority of disruptive variants map to the core α-helical bundle of ACE2 and to residues known to form contacts with the RBD (Figure 4a ). There are two key hotspots in the α-helical bundle of the ACE2 interface that are important for CoV-2 RBD binding: K31 and K353 (Figure 4a, right panel) . To enable interaction with the virus, these charged residues need to be accommodated in a largely hydrophobic environment at the binding interface and hence their neutralization is critical to the binding of coronavirus RBDs to human ACE2 (Li, 2008; Shang et al., 2020; Wu et al., 2012) . A recent elegant study showed that SARS-CoV-2 S-protein is more effective in neutralization of the lysine hotspots than SARS-CoV due to the presence of Q493 and L455 that stabilize K31, and N501 that stabilizes K353, (Figure 4A, right panel) . Interestingly, K31R is one of the human ACE2 polymorphisms that we identified (Supplementary Table 2) . Introduction of an arginine not only maintains the positive charge at position 31 but is also predicted to break an interaction with Q493 in the RBD (Supplementary Figure 5a) and destabilize the charge-neutralizing interaction with the virus. Thus, individuals carrying K31R ACE2 variants are predicted to be less prone to SARS-CoV-2 infection. While we . 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 It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .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 did not identify any polymorphic variants at residue K353, we detected an ACE2 mutation that changes the identity of D38 residue (Supplementary Table 2) , which forms an electrostatic interaction with K353 (Supplementary Table 4) . This mutation (D38V) would compromise the neutralizing effect of the K353-D38 interaction at the interface and is predicted to significantly reduce binding affinity between the virus and the host receptor.