A recent study by US researchers shows how the 501Y.V2 variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), characterized by several mutations, is able to escape neutralization by presenting anti-SARS-CoV- first wave 2 antibodies and potentially reinfect convalescent COVID-19 individuals. The article is currently available on bioRxiv * prepress server.
As many variants of SARS-CoV-2 emerge and subsequently displace first wave viruses, it is critical not only to assess their relative transmissibility and virulence in the cause of coronavirus disease (COVID-19), but also their propensity to escape neutralization. antibodies.
Of greatest interest are variants that harbor mutations that can affect the interaction of the viral peak receptor (S RBD) binding domain with the viral receptor in host cells, the angiotensin-converting enzyme 2 (ACE2), which provides a entry for coronavirus.
Variants with higher binding affinity for ACE2 are likely to spread more. In addition, transmissibility is linked to mortality, as an inevitable increase in infection rates caused by the new variants will result in higher illnesses and deaths.
However, these dire repercussions of faster and more widespread infections can also be exacerbated by a loss of efficacy from currently available antibody-based vaccines and treatments and a decrease in protective immunity in individuals previously infected with a ‘first wave’ virus.
In order to improve our understanding of the risks posed by an individual or combined mutations in these ‘second wave’ variants, a research group from ImmunityBio in California conducted a computational analysis of the interactions of S RBD with human ACE2.
The K484 substitution in the new South African variant increases the affinity of the peak receptor binding domain (S RBD) for ACE2. (a, b) The positions of the substitutions E484K (red), K417N (cyan) and N501K (purple) in the interface of the interface 501Y.V2 variant S RBD – hACE2 are shown. The hACE2 residues closest to the mutated RBD residues are processed as thin sticks. The E484K mutation is located in a highly flexible loop region of the interface, K417N in a region with the least probability of contact and N501K in a second high affinity contact point. (c) The range of motion available for the loop containing residue 484 is shown by the PCA of the MD simulation of a first wave sequence11,13. (d) MD simulation performed in the presence of all 3 substitutions reveals that the loop region is strongly associated (black arrow) with hACE2. A pair of key contact ions is circulated. (e) In comparison with K484, when E484 (‘wild type’) is present only with the Y501 variant, the loop is not as strongly associated (arrow).
In silica simulation methods
In this study, the researchers used millisecond-scale MD simulation methods to investigate mutations (E484K, K417N and N501Y) at the S RBD-ACE2 interface in the 501Y.V2 South African fast-spreading variant – and their effects on binding affinity of RBD and peak glycoprotein conformation.
The wild-type ACE2 / RBD complex was built from the cryoelectronic microscopy structure. In addition, ten copies of each mutant RBD were minimized, balanced and simulated, and the minimization processed occurred in two phases.
Finally, the principal component analysis (PCA) was performed using the complete set of simulations of the triple mutant, E484K and N501Y systems. The simulation structures were extrapolated to the eigenvectors of each mutation system.
The great escape from neutralization
The study revealed a greater affinity of K484 S RBD for ACE2 compared to E484, as well as a higher probability of modified conformation when compared to the original structure. In fact, this may represent the mechanisms by which the new viral variant 501Y.V2 was able to replace the original SARS-CoV-2 strains.
More specifically, both E484K and N501Y mutations showed an increase in the affinity of S RBD for the human ACE2 receptor, while E484K was able to switch the charge in the flexible loop region of RBD, resulting in the formation of new favorable contacts.
The improved affinity mentioned above is a likely culprit for a faster spread of this variant due to its greater transmissibility, which is the main reason why it is important to track these mutations and act in a timely manner.
In addition, the induction of conformational changes is responsible for escaping the 501Y.V2 variant (distinct from the B.1.1.7 UK variant by the presence of the E484K mutation) from neutralizing existing anti-SARS-CoV-2 antibodies and re-infecting individuals COVID-19 convalescents.
Implications for additional vaccine design
“We believe that the DM simulation approach used here similarly represents a tool to be used in the arsenal against the ongoing pandemic, as it provides insight into the likelihood of mutations alone or in combination can have effects that decrease the effectiveness of therapies or existing vaccines, “say the authors of this study.
“We suggest that vaccines whose efficacy is largely dependent on humoral responses to S antigen are inherently limited by the emergence of new strains and dependent on frequent redesigns,” they add.
On the other hand, a vaccine that evokes a vigorous T cell response is much less subject to change due to the accumulation of mutations and thus provides a better and more efficient approach to protection against this disease.
Finally, the ideal vaccine would also incorporate a second conserved antigen (such as the SARS-CoV-2 nucleocapsid protein), which is likely to elicit an effective, cell-mediated humoral immune response – even when confronted with a rapidly changing virus.
* Important news
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, guide clinical practice / health-related behavior or treated as established information.