Emerging of composition variations of SARS-CoV-2 spike protein and human ACE2 contribute to the level of infection: in silico approaches

Abstract

SARS-CoV-2 is causative of pandemic COVID-19. There is a sequence similarity between SARS-CoV-2 and SARS-CoV; however, SARS-CoV-2 RBDs (receptor-binding domain) binds 20-fold strongly with human angiotensin-converting enzyme 2 (hACE2) than SARS-CoV. The study aims to investigate protein–protein interactions (PPI) of hACE2 with SARS-CoV-2 RBD between wild and variants to detect the most influential interaction. Variants of hACE2 were retrieved from NCBI and subjected to determine the most pathogenic nsSNPs. Probability of PPIs determines the binding affinity of hACE2 genetic variants with RBD was investigated. Composition variations at the hACE2 and RBD were processed for PatchDock and refined by FireDock for the PPIs. Twelve nsSNPs were identified as the top pathogenic from SNPs ( n = 7489) in hACE2 using eight bioinformatics tools. Eight RBD variants were complexed with 12 nSNPS of hACE2, and the global energy scores (Kcal/mol) were calculated and classified as very weak (–3.93 to −18.43), weak (–18.42 to −32.94), moderate (–32.94 to −47.44), strong (–47.44 to −61.95) and very strong (–61.95 to −76.46) zones. Seven composition variants in the very strong zone [G726R-G476S; R768W-V367F; Y252N-V483A; Y252N-V367F; G726R-V367F; N720D-V367F and N720D-F486L], and three in very weak [P263S-S383C; RBD-H378R; G726R-A348T] are significantly ( p < 0.00001) varied for global energy score. Zonation of the five zones was established based on the scores to differentiate the effect of hACE2 and RBD variants on the binding affinity. Moreover, our findings support that the combination of hACE2 and RBD is key players for the risk of infection that should be done by further laboratory studies. Communicated by Ramaswamy H. Sarma

Molecular dynamic study of SARS-CoV-2 with various S protein mutations and their effect on thermodynamic properties

“…The COVID-19 illness severity has been classified into five zones based on the primary cause (very weak, weak, moderate, strong and very strong). The wild hACE2 receptor and the SARS-CoV-2 spike protein have a tight binding relationship [ 18 ]. A recent study showed that changes in the pH value of 6.5, 7.4, and 8.0 create several conformation states [ 19 ].…”

In Silico Analysis of High-Risk Missense Variants in Human ACE2 Gene and Susceptibility to SARS-CoV-2 Infection

“…Statistical Analysis and Cumulative Score Calculation of Pathogenic nsSNPs. In order to predict the high-risk pathogenic nsSNPs of human ACE2, the cumulative score for all software tools (SIFT, PolyPhen2.0, PROVEAN, PANTHER, MUpro, I. Mutant, and ModPred) was calculated by using the Sum function in Excel [21]. Then, we set a restricted cumulative score value; when the result of the seven software tools were combined, the amino acid substitution that was evaluated to be deleterious by at least 6 tools would be identified as ACE2 high-risk pathogenic nsSNPs.…”

Identification of natural compounds as SARS-CoV-2 inhibitors via molecular docking and molecular dynamic simulation

“…The SARS-CoV-2 S protein, transmembrane protease serine 2 (TMPRSS2), and human receptor ACE2 are the main determinants of host pathogens affecting infection. The amino acid mutation of S protein, TMPRSS2, and ACE2 binding sites changed the protein affinity, which may affect the structural stability of the complex ( Beacon et al, 2021 ; AlGhamdi et al, 2022 ). Therefore, S glycoprotein and host cell receptor ACE2 are one of the drug targets of SARS-CoV-2.…”