A Computational Approach to Evaluate the Combined Effect of SARS-CoV-2 RBD Mutations and ACE2 Receptor Genetic Variants on Infectivity: The COVID-19 Host-Pathogen Nexus

Abstract

SARS-CoV-2 infectivity is largely determined by the virus Spike protein binding to the ACE2 receptor. Meanwhile, marked infection rate differences were reported between populations and individuals. To understand the disease dynamic, we developed a computational approach to study the implications of both SARS-CoV-2 RBD mutations and ACE2 polymorphism on the stability of the virus-receptor complex. We used the 6LZG PDB RBD/ACE2 3D model, the mCSM platform, the LigPlot+ and PyMol software to analyze the data on SARS-CoV-2 mutations and ACE variants retrieved from GISAID and Ensembl/GnomAD repository. We observed that out of 351 RBD point mutations, 83% destabilizes the complex according to free energy (ΔΔG) differences. We also spotted variations in the patterns of polar and hydrophobic interactions between the mutations occurring in 15 out of 18 contact residues. Similarly, comparison of the effect on the complex stability of different ACE2 variants showed that the pattern of molecular interactions and the complex stability varies also according to ACE2 polymorphism. We infer that it is important to consider both ACE2 variants and circulating SARS-CoV-2 RBD mutations to assess the stability of the virus-receptor association and evaluate infectivity. This approach might offers a good molecular ground to mitigate the virus spreading.

How Concerning Is a Sars-Cov-2 Variant of Concern? Computational Predictions and the Variants Labeling System

“…Delta has only two mutations that occurs out of the contact residues with a stabilizing effect on the complex and hence increasing affinity to ACE2 and an accumulative ΔΔG= −0.33. The single contact residue mutation of the alpha variant (N501Y) showed destabilizing effect that we reported previously (Ashoor et al, 2021) (Table 5).…”

“…Indeed, SARS-CoV-2 is a positive RNA virus that is constantly evolving through the accumulation of various type of mutations (Zhao et al, 2020; Banoun, 2021; Majumdar and Niyogi, 2021; Singh et al, 2021). Even though the majority of these mutations do not affect the virus infectious properties and have no real impact on the progress of the pandemic (Ashoor et al, 2021), some may enhanced specific viral attributes that give the virus a selective advantage (Gobeil et al, 2021). Any new variant endowed with selective advantage(s) would favor the virus persistence and nurture the pandemic.…”

SARS-CoV-2: Emergence of New Variants and Effectiveness of Vaccines

“…including P681H, N501Y, 69/70, E484K, and ORF8 mutations (Collier et al, 2021;Kerneís et al, 2021;Seghatchian, 2021). Another mutation F888L in the spike protein was also identified in the Nigerian variant along with the E484K (Port et al, 2021;Ashoor et al, 2021). This mutation has been reported to alter the biological efficiency of SARS-CoV-2 by performing the hydrolysis by TMPRSS2 and augmenting viral invasion (Ashoor et al, 2021;.…”

“…Another mutation F888L in the spike protein was also identified in the Nigerian variant along with the E484K (Port et al, 2021;Ashoor et al, 2021). This mutation has been reported to alter the biological efficiency of SARS-CoV-2 by performing the hydrolysis by TMPRSS2 and augmenting viral invasion (Ashoor et al, 2021;. It is also probable that this major variation supports the viruses' misleading of the immune response of the host (Kerneís et al, 2021;Liu J et al, 2021;Quinonez et al, 2021).…”

How concerning is a SARS-CoV-2 variant of concern? Computational predictions and the variants labeling system

“…Indeed, SARS-CoV-2 is a positive RNA virus that is constantly evolving through the accumulation of various type of mutations ( Zhao et al., 2020 ; Banoun, 2021 ; Majumdar and Niyogi, 2021 ; Singh et al., 2021 ). Even though the majority of these mutations do not affect the virus infectious properties and have no real impact on the progress of the pandemic ( Ashoor et al., 2021 ), some may enhance specific viral attributes that give the virus a selective advantage ( Gobeil et al., 2021 ). Any new variant endowed with selective advantage(s) would favor the virus persistence and nurture the pandemic.…”