Computational Mutagenesis at the SARS-CoV-2 Spike Protein/Angiotensin-Converting Enzyme 2 Binding Interface: Comparison with Experimental Evidence

Abstract

The coronavirus disease-2019 (COVID-19) pandemic, caused by the pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), started in China during late 2019 and swiftly spread worldwide. Since COVID-19 emergence, many therapeutic regimens have been relentlessly explored, and although two vaccines have just received emergency use authorization by different governmental agencies, antiviral therapeutics based neutralizing antibodies and small-drug inhibitors can still be vital viable options to prevent and treat SARS-CoV-2 infections. The viral spike glycoprotein (S-protein) is the key molecular player that promotes human host cellular invasion via recognition of and binding to the angiotensin-converting enzyme 2 gene (ACE2). In this work, we report the results obtained by mutating in silico the 18 ACE2 residues and the 14 S-protein receptor binding domain (S-RBD CoV-2 ) residues that contribute to the receptor/viral protein binding interface. Specifically, each wild-type protein–protein interface residue was replaced by a hydrophobic (isoleucine), polar (serine and threonine), charged (aspartic acid/glutamic acid and lysine/arginine), and bulky (tryptophan) residue, respectively, in order to study the different effects exerted by nature, shape, and dimensions of the mutant amino acids on the structure and strength of the resulting binding interface. The computational results were next validated a posteriori against the corresponding experimental data, yielding an overall agreement of 92%. Interestingly, a non-negligible number of mis-sense variations were predicted to enhance ACE2/S-RBD CoV-2 binding, including the variants Q24T, T27D/K/W, D30E, H34S7T/K, E35D, Q42K, L79I/W, R357K, and R393K on ACE2 and L455D/W, F456K/W, Q493K, N501T, and Y505W on S-RBD CoV-2 , respectively.

Investigation of nonsynonymous mutations in the spike protein of SARS-CoV-2 and its interaction with the ACE2 receptor by molecular docking and MM/GBSA approach

“…This confirms and provides evidence that was stabilizing nonsynonymous mutations have a high affinity with ACE2 and high virulent levels compared to native and destabilizing nonsynonymous mutations of the S-protein. There is some experimental evidence to corroborate our findings, which proves the better association between ACE2 and S-protein upon stabilizing nonsynonymous mutations [ [79] , [80] , [81] , [82] , [83] , [84] ]. Many recent studies reported that mainly the stabilizing nonsynonymous mutations N501Y and D614G have a better affinity with the ACE2 receptor [ [73] , [74] , [75] , [76] , [79] , [80] , [81] , [82] , [83] , [84] ].…”

“…There is some experimental evidence to corroborate our findings, which proves the better association between ACE2 and S-protein upon stabilizing nonsynonymous mutations [ [79] , [80] , [81] , [82] , [83] , [84] ]. Many recent studies reported that mainly the stabilizing nonsynonymous mutations N501Y and D614G have a better affinity with the ACE2 receptor [ [73] , [74] , [75] , [76] , [79] , [80] , [81] , [82] , [83] , [84] ]. This result will help experimental scientists understand the mechanism of the S-protein and its interaction with the ACE2 receptor upon nonsynonymous mutations.…”

What Binds Cationic Photosensitizers Better: Brownian Dynamics Reveals Key Interaction Sites on Spike Proteins of SARS-CoV, MERS-CoV, and SARS-CoV-2

“…Computational virology tools contribute greatly to the understanding of viral structure, infectivity and pathogenesis, and design of antiviral drugs. Computational mutagenesis revealed key mutations that affect the electrostatic properties of coronavirus spikes and RBD binding interface [ 30 , 31 ]. Molecular Dynamics (MD) and Monte Carlo simulations shed light on the molecular interactions of the coronavirus RBD domain with host receptors and antibodies [ 32 ], and factors that influence the fusion process [ 33 ], as well as contributed to the design of antiviral peptides [ 34 ].…”

Molecular Level Dissection of Critical Spike Mutations in SARS‐CoV‐2 Variants of Concern (VOCs): A Simplified Review

“…However, many computational investigations/simulations/analysis are available in literature where researchers have artificially mutated the standard wild type protein and then using this model they have examined the mutational consequences. [26][27][28] So far, only partial understanding of the molecular reasons leading towards enhanced infection and cellular uptake of new SARS-CoV-2 variants of concerns (VOCs) like B.1.1.7 (alpha), B.1.351 (beta), P.1(gamma) and B.1.617.2 (delta) lineages exists. Until detailed experimental data about structures of mutated spike protein of these new variants and their bound complexes becomes available, computational mutagenesis/simulation studies are the only asset to combat with these new variants of SARS-CoV-2.…”