Higher infectivity of the SARS‐CoV‐2 new variants is associated with K417N/T, E484K, and N501Y mutants: An insight from structural data

Abstract

The evolution of the SARS‐CoV‐2 new variants reported to be 70% more contagious than the earlier one is now spreading fast worldwide. There is an instant need to discover how the new variants interact with the host receptor (ACE2). Among the reported mutations in the Spike glycoprotein of the new variants, three are specific to the receptor‐binding domain (RBD) and required insightful scrutiny for new therapeutic options. These structural evolutions in the RBD domain may impart a critical role to the unique pathogenicity of the SARS‐CoV‐2 new variants. Herein, using structural and biophysical approaches, we explored that the specific mutations in the UK (N501Y), South African (K417N‐E484K‐N501Y), Brazilian (K417T‐E484K‐N501Y), and hypothetical (N501Y‐E484K) variants alter the binding affinity, create new inter‐protein contacts and changes the internal structural dynamics thereby increases the binding and eventually the infectivity. Our investigation highlighted that the South African (K417N‐E484K‐N501Y), Brazilian (K417T‐E484K‐N501Y) variants are more lethal than the UK variant (N501Y). The behavior of the wild type and N501Y is comparable. Free energy calculations further confirmed that increased binding of the spike RBD to the ACE2 is mainly due to the electrostatic contribution. Further, we find that the unusual virulence of this virus is potentially the consequence of Darwinian selection‐driven epistasis in protein evolution. The triple mutants (South African and Brazilian) may pose a serious threat to the efficacy of the already developed vaccine. Our analysis would help to understand the binding and structural dynamics of the new mutations in the RBD domain of the Spike protein and demand further investigation in in vitro and in vivo models to design potential therapeutics against the new variants.

Preliminary report on SARS-CoV-2 Spike mutation T478K

“…Recombinant vaccines comprising the Spike RBD induced potent antibody response in immunized animal models such as mouse, rabbits and primates [13]. On the other hand, mutations in the RBD can improve viral affinity to ACE2 and the evasion from neutralization antibodies [8,[14][15][16]. A recently published clinical study [17] has shown also a decreased vaccine efficacy against the lineage B.1.351 (carrying Spike mutations E484K and N501Y), testifying the need to track and monitor all SARS-CoV-2 mutations, with a particular accent on those affecting the Spike RBD.…”

Anchor-Locker Binding Mechanism of the Coronavirus Spike Protein to Human ACE2: Insights from Computational Analysis

“…This explains to a certain extent the phenomenon that the well-known N501 mutation will lead to stronger affinity. 44 …”

Insights Into Mutations Induced Conformational Changes and Rearrangement of Fe2+ Ion in pncA Gene of Mycobacterium tuberculosis to Decipher the Mechanism of Resistance to Pyrazinamide

“…In this regard, in silico techniques such as MD simulations were utilized to study the said mutations role in PZase resistance to PZA. These methods are widely used to understand the mechanism of resistance and any binding perturbation caused by mutations ( Khan et al, 2020c , e , 2021a , b ). It unveils conformational changes of proteins caused by any intrinsic mutations or ligand binding.…”