Identification of destabilizing SNPs in SARS-CoV2-ACE2 protein and spike glycoprotein: implications for virus entry mechanisms

Abstract

COVID-19 an outbreak of a novel corona virus originating from Wuhan, China in December 2019 has now spread across the entire world and has been declared a pandemic by WHO. Angiotensin converting enzyme 2 (ACE2) is a receptor protein that interacts with the spike glycoprotein of the host to facilitate the entry of coronavirus (SARS-CoV-2) hence causing the disease (COVID-19). Our experimental design is based on bioinformatics approach that combines sequence, structure and consensus based tools to label a protein coding single nucleotide polymorphism (SNP) as damaging/deleterious or neutral. The interaction of wildtype ACE2-spike glycoprotein and their variants were analyzed using docking studies. The mutations W461R, G405E and F588S in ACE2 receptor protein and population specific mutations P391S, C12S and G1223A in the spike glycoprotein were predicted as highly destabilizing to the structure of the bound complex. So far, no extensive in silico study has been reported that identifies the effect of SNPs on Spike glycoprotein-ACE2 interaction exploring both sequence and structural features. To this end, this study conducted an in-depth analysis that facilitates in identifying the mutations that blocks the interaction of two proteins that can result in stopping the virus from entering the host cell.

A systematic review of nonsynonymous single nucleotide polymorphisms in the renin–angiotensin–aldosterone system

“…Since angiotensin converting enzyme 2 interacts with spike glycoprotein of the host to facilitate COVID-19 virus entry to the cells, Khalid et al [ 21 ], carried out an in-silico study to determine the effect of SNPs at ACE2 gene on tertiary structure of this protein and the impact of these SNPs on binding the virus. Two variants in ACE2 were identified as those which have an influence on the repulsion of ligands of the same negative charge (G405E, W461R), and the third was probably damaging to the protein (F588S).…”

“…Two variants in ACE2 were identified as those which have an influence on the repulsion of ligands of the same negative charge (G405E, W461R), and the third was probably damaging to the protein (F588S). These findings may explain the differences in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-related disease during the current pandemic [ 21 ].…”

Insights into the structure and dynamics of SARS-CoV-2 spike glycoprotein double mutant L452R-E484Q

“…However, mechanistic and functional consequences of amino acid substitutions remain unresolved (Mishra et al 2021;Teng et al 2021). Khalid et al, 2020 reported an in-depth study on spike glycoprotein-ACE2 interactions exploring both sequence and structural features using a bioinformatics approach. The authors labeled various single nucleotide polymorphism (SNP) as damaging/deleterious/destabilizing that block the interaction, which might halt the virus from entering the host cell (Khalid and Naveed 2020).…”

“…Khalid et al, 2020 reported an in-depth study on spike glycoprotein-ACE2 interactions exploring both sequence and structural features using a bioinformatics approach. The authors labeled various single nucleotide polymorphism (SNP) as damaging/deleterious/destabilizing that block the interaction, which might halt the virus from entering the host cell (Khalid and Naveed 2020). Ahmed et al reported mutations occurring in the proteins can affect its conformation, structure folding and stability, which can eventually show effect on protein-protein interactions/ thermodynamics.…”

Host polymorphisms and COVID-19 infection

“…DOCK and FireDock simulations identified 6 ACE2 missense variants (A25T, E37K, E75G, I21T, K26R, T55A) with higher affinity for SARS-CoV-2 Spike protein receptor-binding domain for wild type ACE2, and 11 variants (E23K, E35K, I21V, K26E, K68E, M82I, N51D, N58H, S43R, T27A, Y50F) with a lower affinity [18] . An in-silico study showed that mutations W461R, G405E and F588S in ACE2 receptor protein and population-specific mutations P391S, C12S, and G1223A in the spike glycoprotein were predicted as highly destabilizing to the structure of the bound complex [19] .…”