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 the current anti- SARS-CoV first wave 2 antibodies and potentially re-infect COVID-19 convalescent people. The document is currently available at bioRxiv * prepress server.
Because 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 causing coronavirus disease (COVID-19), but also their propensity to flee from neutralizing antibodies.
Of maximum interest are variants containing mutations that may affect the interaction of the spike viral receptor binding domain (S RBD) with the host cell viral receptor, the angiotensin-converting enzyme 2 ( ACE2), which provides an entry point for the coronavirus.
It is likely that variants with a higher binding affinity for ACE2 will spread more. In addition, transmissibility is related to mortality, as an inevitable increase in infection rates caused by the new variants will lead to a higher number of diseases and mortality.
However, these terrible repercussions of faster and more widespread infections can also be exacerbated by a loss of efficacy of currently available antibody-based treatments and vaccines and a decrease in protective immunity in individuals previously infected with a virus. first wave ”.
In order to improve our understanding of the risks of individual or combined mutations in these “second wave” variants, a research group from the company ImmunityBio in California conducted a computational analysis of the interactions of S RBD with human ACE2. .
Substitution of K484 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 substitutions E484K (red), K417N (cyan) and N501K (violet) are shown at the interface of variant 501Y.V2 S RBD – hACE2 interface. The hACE2 residues closest to the mutated RBD residues are represented as thin sticks. The E484K mutation is located in a highly flexible loop region of the interface, K417N in a region with a lower probability of contact, and N501K in a second high-affinity point of contact. (c) The range of motion available for the loop containing residue 484 is shown by the PCA simulation of MD of a first-wave sequence11,13. (d) The MD simulation performed in the presence of the 3 substitutions reveals that the loop region is closely associated (black arrow) with hACE2. A pair of key contact ions are circled. (e) Compared to K484, when E484 (‘wildtype’) is only present with variant Y501, the loop is not so closely associated (arrow).
In silico simulation methods
In this study, researchers used millisecond-scale MD simulation methods to investigate mutations (E484K, K417N, and N501Y) at the RBD-ACE2 S interface in the rapidly expanding South African variant 501Y.V2 – i its effects on RBD binding affinity and glycoprotein conformation.
The wild-type ACE2 / RBD complex was constructed from the structure of cryocomputer microscopy. In addition, ten copies of each RBD mutant were minimized, balanced, and simulated, and the processed minimization occurred in two phases.
Finally, 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 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 actually represent mechanisms by which the new viral variant 501Y.V2 was able to replace the original SARS-CoV-2 strains.
More specifically, in both the E484K and N501Y mutations a higher affinity for S RBD was shown for the human ACE2 receptor, whereas E484K was able to change the charge in the RBD flexible loop region, resulting in the formation of RBD. us favorable contacts.
The enhanced affinity mentioned is likely to be to blame for a faster spread of this variant due to increased transmissibility, which is one of the main reasons why it is important to monitor these mutations and act on them. timely manner.
In addition, the induction of conformational changes is responsible for the escape of variant 501Y.V2 (distinguished from variant B.1.1.7 of the United Kingdom by the presence of the E484K mutation) from the neutralization by anti-SARS antibodies- Existing CoV-2 and re-infect COVID-19 convalescent people.
Implications for subsequent vaccine design
“We believe that the MD simulation approach used here represents a tool to be used in the arsenal against the ongoing pandemic, as it provides information on the likelihood that single or combined mutations may have effects that diminish the pandemic. effectiveness of existing therapies or vaccines, ”say the authors of this study.
“We suggest that vaccines whose effectiveness depends largely on humoral responses to S antigen are only intrinsically limited by the emergence of new strains and depend on frequent redesign,” they add.
On the other hand, a vaccine that evokes a vigorous T cell response is much less subject to change due to accumulated mutations and therefore 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 would likely elicit an effective humoral, cell-mediated immune response, even when faced with a changing virus. quickly.
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