Most Deleterious Missense Variants of Angiotensin-converting Enzyme 2 Gene have Extremely Low Frequencies and a Little Impact on the Binding Affinity with the SARS-CoV-2 Spike

Abstract

Angiotensin-converting enzyme 2 (ACE2) is a well-established functional host receptor for the highly devastating ongoing pandemic of coronavirus disease 2019 (COVID-19). This protein provides the entry point through which COVID-19 hooks and infects human cells. A damaged ACE2 could alter the rate of this viral infection. This study was conducted to predict the most deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) on ACE2, assess their frequency among populations, and evaluate their effect on the binding with the SARS-CoV-2 spike. All sequence-based in silico tools indicated damaging impacts of V184G, A191P, P235R, P263S, G268C, G377E, Y515C, G466W, and L595V. Structure-based tools showed damaging effects of C141Y, Y158H, G173D, Y207C, I233N, Y252C, Y252N, L291K, M376T, G377E, M383T, N397D, E398K, G405E, L418S, N437H, G448E, W461R, V463D, Y515C, I544N, L570S, L585P, F588S, and N599K. All these risky amino acid alterations were found in extremely low-frequency worldwide. Docking showed few effects of these nsSNPs in altering the binding affinity of ACE2 with SARS-CoV-2 spike. G377E and Y515C showed the highest damaging impacts on the biological activity of ACE2. Though Y515C caused higher affinity than other risky SNPs to bind with spike, no remarkable alteration was observed in this interaction. This entails that the risky SNPs of ACE2 exert low-frequency deleterious impacts on this enzyme without being necessarily involved in the interaction with SARS-CoV-2 spike. To the best of our knowledge, this is the first comprehensive computation that predicted the low effectiveness of altering the ACE2-spike interaction due to the distant positions they occupy away from ACE2-spike interactions.