Allelic Variations in ACE2 and Natural Resistance against COVID-19

Introduction: Genetic variations are arguably the most crucial driver that under pins the evolutionary arms race between pathogens and their host. Where variations in the pathogen may lead to the origin of new and more virulent strains, variations in the host may confer resistance against emerging pathogens. Often the genetic variations under neutral selection found its purpose with the origin of new kind of selection pressure. SARS-CoV-2 represents itself a noticeable form of natural selection and variations in its host receptor, ACE2, may confer resistance against the infection. This study aims to investigate the same.

Methodology: Briefly, coding variants of human ACE2 corresponding to the critical binding sites between ACE2-SARS‐CoV, ACE2‐SARS‐CoV‐2 (PDBid: 6LZG), and those reported to show impaired binding with coronavirus spike protein in the in vitro mutation analysis were selected for investigations. Stability and pathogenic effect of the amino acid substitution in ACE2 were predicted using i-Mutant, SIFT, PolyPhen-2, CADD and REVEL. Molecular models of all ACE2 variants were developed and docking pose with SARS-CoV-2 spike protein were generated by Cα back bone superimposition. ACE2-SARS-CoV-2 S protein complexes were further assessed for intermolecular interactions and binding energies.

Results: Thermodynamically, amino acid substitutions in three alleles, rs73635825 (S19P), rs1299103394 (K26E), and rs766996587 (M82I) may destabilize the encoded protein of ACE2 variant compared to wild type. Moreover, except for rs73635825 (S19P), which was predicted to be damaging by only PolyPhen‐2, rs961360700 (D355N) and rs762890235 (P389H) were predicted to be detrimental by SIFT and Polyphen‐2, whereas rs1396769231 (M383T) was predicted to be damaging by SIFT, Polyphen‐2, and REVEL prediction tools. The overall protein conformation of ACE2 allelic variants is largely conserved with RMSD of Cα backbone ranges from 0.17 to 0.58 Å, compared with the wild type. All ACE2 variants were interacts with viral spike protein with nearly identical topology to the resolved ACE2‐SARS‐CoV‐2 complex structure. Amongst the most conserved intermolecular interactions (hydrogen bonds) between different ACE2 variants and SARS‐CoV‐2 spike protein are: Y41, H34, Y83, and K353 of ACE2 and T500, Y453 (except M82I), N487 (except T27A and D427Y), and G502 (except S19P and E329G) of SARS‐CoV‐2 spike protein, respectively. Binding affinity of the S19P and E329G of ACE2 variant for SARS‐CoV‐2 spike protein were also predicted to be amongst the lowest −10.3 and −10.8 for SARS‐CoV‐2 spike protein.

Conclusion: Clinical manifestations and recovery rate of COVID‐19 varies noticeably between different age groups, nationalities, and race. The present investigation indicates the candidate alleles of ACE2 that could affect the susceptibility and/or resistance against COVID‐19. It is plausible that the positive prognosis of the COVID‐19 in some individuals may be rendered by the predicted allelic variants of ACE2.