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A recent study by American researchers shows how the 501Y.V2 variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), characterized by several mutations, is able to escape neutralization by the current anti- SARS-CoV- 2 antibody and potentially re-infect recovering COVID-19 individuals. The document is currently available on the bioRxiv * pre-print server.
As many variants of SARS-CoV-2 emerge and subsequently displace the first wave viruses, it is essential not only to assess their transmissibility and virulence relating to the origin of the coronavirus disease (COVID-19 ), but also their propensity to escape neutralization of antibodies.
Variants with mutations that may affect the interaction of the viral spike receptor binding domain (S RBD) with the viral receptor on host cells, the angiotensin-converting enzyme 2 (ACE2), which provides an entry point for the coronavirus, are of major interest.
Variants with higher binding affinity for ACE2 are likely to spread further. In addition, transmissibility is linked to mortality, as an inevitable increase in infection rates caused by the new variants will lead to an increase in the number of illnesses and deaths.
However, these terrible repercussions of faster and more widespread infections can also be compounded by a loss of effectiveness of currently available antibody-based treatments and vaccines and by a decrease in protective immunity in people previously infected with a virus. “first wave” virus.
In order to improve our understanding of the risks posed by individual or combined mutations in these “ second wave ” variants, a research group at the company ImmunityBio in California conducted a computer analysis of the interactions of S RBD with the Human ACE2.
The K484 substitution in the new South African variant increases the affinity of the spike receptor binding domain (S RBD) for ACE2. (a, b) The positions of the E484K (red), K417N (cyan) and N501K (purple) substitutions at the interface of the 501Y.V2 variant S RBD – hACE2 interface are indicated. The hACE2 residues closest to the mutated RBD residues are rendered as thin rods. The E484K mutation is located in a very flexible loop region of the interface, K417N in a region with a lower probability of contact and N501K at a second high affinity contact point. (c) The range of motion available for the loop containing residue 484 is represented by MD simulation PCA of a first wave sequence11,13. (d) MD simulation performed in the presence of all 3 substitutions reveals that the loop region is closely associated (black arrow) with hACE2. A pair of key contact ions is circled. (e) Compared to K484, when E484 (“wild type”) is present only with the Y501 variant, the loop is not as closely associated (arrow).
In silico simulation methods
In this study, researchers used millisecond-scale MD simulation methods to study mutations (E484K, K417N, and N501Y) at the RBD-ACE2 S interface in the fast-spreading South African variant 501Y. V2 – and their effects on RBD binding affinity and peak glycoprotein conformation.
The wild type ACE2 / RBD complex was constructed from the cryoelectron microscopy framework. In addition, ten copies of each RBD mutant were minimized, balanced and simulated, and the processed minimization occurred in two phases.
Finally, the principal component analysis (PCA) was continued using the full set of simulations of the triple mutant systems, E484K and N501Y. The simulation structures were extrapolated on the eigenvectors for each mutation system.
The great escape from neutralization
The study revealed a higher affinity of K484 S RBD for ACE2 compared to E484, as well as a higher probability of altered conformation compared to the original structure. This may in fact represent mechanisms by which the new viral variant 501Y.V2 may have replaced the original strains of SARS-CoV-2.
More specifically, the E484K and N501Y mutations showed increased affinity of S RBD for the human ACE2 receptor, while E484K was able to switch the charge on the flexible loop region of RBD, resulting in the formation of new favorable contacts.
The aforementioned enhanced affinity is probably responsible for the faster spread of this variant due to greater transmissibility, which is one of the main reasons why it is important to keep up with these mutations and act in time. timely.
In addition, the induction of conformational changes is responsible for the escape of the 501Y.V2 variant (distinguished from the B.1.1.7 UK variant by the presence of the E484K mutation) from neutralization by anti-SARS-CoV- antibodies. 2 existing ones and re-infect the COVID-19 convalescents.
Implications for subsequent vaccine design
“We believe that the MD simulation approach used here similarly represents a tool to use in the arsenal against the continuing pandemic, as it provides insight into the likelihood that mutations alone or in combination could have effects that reduce the effectiveness of existing therapies or vaccines, “say the authors of this study.
“We suggest that vaccines whose efficacy depends largely on humoral responses to the S antigen alone are inherently limited by the emergence of new strains and depend on frequent rearrangement,” they add.
On the other hand, a vaccine which evokes a vigorous T cell response is much less subject to changes due to growing mutations and, therefore, provides a better and more effective approach to protection against this disease.
Finally, the ideal vaccine would also incorporate a second conserved antigen (like the core protein of SARS-CoV-2), which would likely elicit an effective humoral and cellular immune response – even when faced with a rapidly evolving virus.
*Important Notice
bioRxiv publishes preliminary scientific reports which are not peer reviewed and, therefore, should not be considered conclusive, guide clinical practice / health-related behaviors, or treated as established information.
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