ImmunityBio reported their findings from a follow-up Molecular Dynamics (MD) simulation study of the SARS-CoV-2 spike receptor-binding domain (RBD) and its binding to its receptor on human cells, angiotensin-converting enzyme 2 (ACE2).
In the first study, “Millisecond-scale molecular dynamics simulation of spike RBD structure reveals evolutionary adaption of SARS-CoV-2 to stably bind ACE2” using exceptionally long-duration millisecond scale MD simulation, ImmunityBio scientists revealed the evolutionary adaptation of spike RBD for binding to ACE2, and the regions of RBD that strongly bind ACE2. These findings provide targets for potential new therapeutics or vaccines.
In the new study, MD simulation was applied to the highly concerning new strains of SARS-CoV-2 including the predominating variant in South Africa 501Y.V2 and the UK variant B.1.1.7. The simulations were focused on the mutations found at the interface of the spike RBD and ACE2, E484K, K417N, and N501Y, because these mutations are highly likely to affect binding and thus transmissibility. Indeed, both E484K and N501Y were found to increase affinity of RBD binding to ACE2.
A very notable finding of the simulations was that the combination of E484K, K417N and N501Y, found only in the South African variant, results in the highest degree of conformational alterations of S RBD when bound to hACE2, compared to either E484K or N501Y alone. Conformation affects the recognition of an antibody to an antigen site.
Enhanced affinity of S RBD for hACE2 very likely underpins the greater transmissibility conferred by the presence of either E484K or N501Y; while the induction of conformational changes may provide an explanation for evidence that the 501Y.V2 variant, distinguished from the B.1.1.7 UK variant by the presence of E484K, is able to escape neutralization by existing first-wave anti-SARS-CoV-2 antibodies and re-infect COVID-19 convalescent individuals.
The manuscript and a video detailing the findings of the ImmunityBio molecular dynamic simulation studies is available on preprint server bioRxiv and is concurrently undergoing scientific peer-review for publication.