Predicting the feasibility of targeting a conserved region on the S2 domain of the SARS-CoV-2 spike protein

The efficacy of vaccines against the SARS-CoV-2 virus significantly declines with the emergence of mutant strains, prompting investigation into the feasibility of targeting highly conserved but often cryptic regions on the S2 domain of spike protein. Using tools from molecular dynamics, we find that this conserved S2 epitope located in the central helices below the receptor binding domains is unlikely to be exposed by dynamic fluctuations without any external facilitating factors, in spite of previous computational evidence suggesting transient exposure of this region. Furthermore, glycans inhibit opening dynamics, and thus stabilize spike in addition to immunologically shielding the protein surface, again in contrast to previous computational findings. Though the S2 epitope region examined here is central to large scale conformational changes during viral entry, free energy landscape analysis obtained using the path coordinate formalism reveals no inherent "loaded spring" effect, suggesting that a vaccine immunogen would tend to present the epitope in a pre-fusion-like conformation and may be effective in neutralization. These findings contribute to a deeper understanding of the dynamic origins of the function of the spike protein, as well as further characterizing the feasibility of the S2 epitope as a therapeutic target.