A recent study by US researchers shows how variant 501Y.V2 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), characterized by several mutations, is able to escape neutralization by anti-SARS-CoV 2 antibodies and can reinforce convalescent individuals COVID-19. The paper is currently available on bioRxiv * prepress server.
As numerous variants of SARS-CoV-2 appear and subsequently replace first-wave viruses, it is essential not only to assess their transmissibility and virulence relative to coronavirus disease (COVID-19), but also their tendency to escape neutralization. antibodies.
Of great interest are variants containing mutations that may affect the interaction of the viral receptor binding domain (S RBD) with the viral receptor on host cells, the angiotensin 2 conversion enzyme (ACE2), which provides an entry point for coronavirus.
Variants with a higher binding affinity for ACE2 are likely to be more widespread. Moreover, 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 diseases and deaths.
However, these serious repercussions of faster and more widespread infections may also be exacerbated by a loss of efficacy of currently available antibody-based treatments and vaccines and a decrease in protective immunity in people previously infected with a virus. ” the first wave ”.
To improve our understanding of the risks posed by an individual or combined mutation in these “second wave” variants, a research group from California-based ImmunityBio conducted a computational analysis of S RBD interactions with human ACE2.
Substitution K484 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) at the 501Y.V2 interface variant S RBD – hACE2 interface are displayed. the hACE2 residues closest to the mutant RBD residues are rendered in the form of 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 in a second point of contact with high affinity. (c) The range of motion available for the loop containing residue 484 is shown by the PCA simulation of the MD of a sequence from the first wave11,13. (d) The MD simulation performed in the presence of the 3 substitutions shows that the loop region is closely associated (black arrow) with hACE2. A pair of key contact ions is encircled. (e) Compared to K484, when E484 (‘wildtype’) is present only with variant Y501, the loop is not as closely associated (arrow).
In Silicon simulation methods
In this study, the researchers used millisecond-scale MD simulation methods to investigate mutations (E484K, K417N, and N501Y) at the RBD-ACE2 S interface in the fast-growing 501Y.V2 South African variant – and their effects on affinity for RBD binding and spike glycoprotein conformation.
The wild-type ACE2 / RBD complex was constructed from the structure of cryo-electron microscopy. Moreover, ten copies of each RBD mutant were minimized, balanced, and simulated, and the processed minimization took place in two phases.
Finally, the principal component analysis (PCA) was followed using the complete set of simulations of the triple mutant systems, E484K and N501Y. The simulation structures were extrapolated to 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 modified conformation compared to the original structure. This may in fact represent mechanisms by which the new viral variant 501Y.V2 managed to replace the original SARS-CoV-2 strains.
More specifically, both E484K and N501Y mutations were shown an increased affinity of S RBD for the human ACE2 receptor, while E484K was able to switch the load on the flexible loop region of the RBD, resulting in the formation of new favorable contacts.
The enhanced affinity mentioned above is probably to blame for the faster spread of this variant due to the higher transmissibility, which is a key reason why it is important to track these mutations and act in a timely manner.
Furthermore, the induction of conformational changes is responsible for the escape of variant 501Y.V2 (distinguished from variant B.1.1.7 UK by the presence of the E484K mutation) from neutralization by anti-SARS-CoV-2 antibodies and re-infected COVID-19 convalescent individuals .
Implications for subsequent vaccine design
“We believe that the MD simulation approach used here is similarly a tool to be used in the arsenal against the continuous pandemic, as it provides information on the likelihood of mutations, alone or in combination, may have effects that diminish the effectiveness of existing therapies or vaccines,” say the authors. of this study.
“We suggest vaccines whose efficacy depends largely on humoral responses to the S antigen are only inherently limited by the emergence of new strains and dependent on frequent re-design,” they add.
On the other hand, a vaccine that evokes a vigorous T-cell response is much less susceptible to changes due to accumulating mutations and thus offers a better and more effective 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 would elicit an effective humoral and cell-mediated immune response – even when faced with a rapidly changing virus.
*Important Note
bioRxiv publishes preliminary scientific reports that are not evaluated by colleagues and therefore should not be considered conclusive, guide clinical practice / health-related behavior or be treated as established information.