Bioinformatics analysis of the differences in the binding profile of the wild-type and mutants of the SARS-CoV-2 spike protein variants with the ACE2 receptor

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). Reports of new variants that potentially increase virulence and viral transmission, as well as reduce the efficacy of available vaccines, have recently emerged. In this study, we computationally analyzed the N439K, S477 N, and T478K variants for their ability to bind Angiotensin-converting enzyme 2 (ACE2). We used the protein-protein docking approach to explore whether the three variants displayed a higher binding affinity to the ACE2 receptor than the wild type. We found that these variants alter the hydrogen bonding network and the cluster of interactions. Additional salt bridges, hydrogen bonds, and a high number of non-bonded contacts (i.e., non-bonded interactions between atoms in the same molecule and those in other molecules) were observed only in the mutant complexes, allowing efficient binding to the ACE2 receptor. Furthermore, we used a 2.0-μs all-atoms simulation approach to detect differences in the structural dynamic features of the resulting protein complexes. Our findings revealed that the mutant complexes possessed stable dynamics, consistent with the global trend of mutations yielding variants with improved stability and enhanced affinity. Binding energy calculations based on molecular mechanics/generalized Born surface area (MM/GBSA) further revealed that electrostatic interactions principally increased net binding energies. The stability and binding energies of N439K, S477 N, and T478K variants were enhanced compared to the wild-type-ACE2 complex. The net binding energy of the systems was −31.86 kcal/mol for the wild-type-ACE2 complex, −67.85 kcal/mol for N439K, −69.82 kcal/mol for S477 N, and −69.64 kcal/mol for T478K. The current study provides a basis for exploring the enhanced binding abilities and structural features of SARS-CoV-2 variants to design novel therapeutics against the virus.

Computational prediction of the effect of mutations in the receptor-binding domain on the interaction between SARS-CoV-2 and human ACE2

“…The increased affinity for hACE2 may be a contributing factor to the increased SARS-CoV-2's infectivity, which is associated with increased transmission [70]. This is consistent with our previous findings [1] and study of Suleman et al [63] using a different variant, which demonstrated that the presence of mutations in RBD increased the spike binding affinity on hACE2. The complex δ 484 -hACE2 provides the highest level of BFE (−2485.79 kcal/mol).…”

“…Despite the fact that the BFE value from the interaction between RBD and hACE2 via HDOCK and Prodigy was obtained, the BFE calculation using the MM-PBSA method to calculate in-depth atomic-level interaction energy analysis was still performed. This is due to the fact that the BFE value derived from docking results is less accurate [63]. The destabilizing effects of some variants have been previously reported to be associated with enhanced binding because of the fact that mutations with destabilizing effects produce radical functions [57,64].…”

Omicron SARS-CoV-2 Variant Spike Protein Shows an Increased Affinity to the Human ACE2 Receptor: An In Silico Analysis

“…The Alpha variant has a non-synonymous substitution of N501Y, while the Beta variant, as well as Gamma and Mu variants additionally contain the E484K mutation (Table 1). Previous reports showed that these mutations most likely increase the binding affinity of the spike to ACE2 as compared to the WT spike, without affecting its overall structure [13][14][15]. These mutations are located primarily in the protein loops, which due to their high flexibility could likely tolerate the conformational changes associated with the residue substitution.…”

Viral and Host Genetic and Epigenetic Biomarkers Related to SARS-CoV-2 Cell Entry, Infection Rate, and Disease Severity

“…Residues 452, 489, 500, 501, and 505 on the RBM of spike protein ( Figure 3 C) have high chances of mutating into more infective strains [ 27 ]. Suleman et al computed three mutations, N439K, S477 N, and T478K, shown in Figure 3 D, to increase binding with ACE2 [ 28 ]. These mutations are localized on, or close to, the ACE2 binding site, except for D614G, which indirectly enhances ACE2 interaction through spike trimer binding enhancement ( Figure 3 ).…”

“…Bioinformatic predictions data match strain infectivity data. Mutations in strains overlap with the mutations predicted by bioinformatics tools [ 26 , 27 , 28 ].…”