Mutations of SARS-CoV-2 RBD May Alter Its Molecular Structure to Improve Its Infection Efficiency

Abstract

The receptor-binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mediates the viral–host interaction and is a target for most neutralizing antibodies. Nevertheless, SARS-CoV-2 RBD mutations pose a threat due to their role in host cell entry via the human angiotensin-converting enzyme 2 receptor that might strengthen SARS-CoV-2 infectivity, viral load, or resistance against neutralizing antibodies. To understand the molecular structural link between RBD mutations and infectivity, the top five mutant RBDs (i.e., N501Y, E484K L452R, S477N, and N439K) were selected based on their recorded case numbers. These mutants along with wild-type (WT) RBD were studied through all-atom molecular dynamics (MD) simulations of 100 ns. The principal component analysis and the free energy landscape were used too. Interestingly, N501Y, N439K, and E484K mutations were observed to increase the rigidity in some RBD regions while increasing the flexibility of the receptor-binding motif (RBM) region, suggesting a compensation of the entropy penalty. However, S477N and L452R RBDs were observed to increase the flexibility of the RBM region while maintaining similar flexibility in other RBD regions in comparison to WT RBD. Therefore, both mutations (especially S477N) might destabilize the RBD structure, as loose conformation compactness was observed. The destabilizing effect of S477N RBD was consistent with previous work on S477N mutation. Finally, the free energy landscape results showed that mutations changed WT RBD conformation while local minima were maintained for all mutant RBDs. In conclusion, RBD mutations definitely impact the WT RBD structure and conformation as well as increase the binding affinity to angiotensin-converting enzyme receptor.

The Glu143 Residue Might Play a Significant Role in T20 Peptide Binding to HIV-1 Receptor gp41: An In Silico Study

“…This might suggest the requirement of a certain degree of flexibility to maintain T20′s conformation for binding to the gp41 receptor. Moreover, the solvent accessible surface area (SASA) was used to predict conformational changes in WT and mutant proteins [11][12][13]. There was a slight enhancement in the SASA of the E143A mutant compared to WT T20 (Figure 2B).…”

“…The free energy landscape (FEL) of the all-peptide atoms was used to evaluate conformations at minima during the MD simulations [11]. The FEL of the backbone residues was plotted by projecting MD trajectories onto the first two principal components PC1 and PC2 of T20 and the E143A mutant.…”

“…The sequence of the WT T20 peptide was Ac-127 YTSLIHSLIEE SQNQQEKNEQELLELDKWASL 158 , and the N-termini of both WT T20 and the E143E mutant were capped with an acetyl group. The obtained structure of the E143A mutant was validated as described previously [11,12].…”

“…The X-ray structure of WT T20 and the obtained E143A structure were used as a starting coordinate for the simulation systems. Afterward, MD simulations were conducted for both systems following our previous works with slight changes [11,12,17]. Particle mesh Ewald (PME) [18] was used instead of the cutoff scheme, and a short-range non-bonded cutoff distance of 1.3 nm was used to compute the long-range electrostatic interactions.…”

Physicochemical effect of the N501Y, E484K/Q, K417N/T, L452R and T478K mutations on the SARS-CoV-2 spike protein RBD and its influence on agent fitness and on attributes developed by emerging variants of concern

“…Several molecular dynamics studies have demonstrated these effects and their implications for the SARS-CoV-2 variants fitness ( Alaofi and Shahid, 2021 ; Istifli et al, 2021 ; Peters et al, 2021 ). However, in most of these studies the change in the variants' fitness is demonstrated considering the combined mutations effect (or the set of them) identified in the VOCs, which limits the understanding of the effect and impact caused by each one of them individually.…”