In a study by Garg et al., the Plotkin lab has investigated the feasibility of targeting evolutionarily conserved regions inside the SARS-CoV-2 spike protein. These conserved regions are normally buried, but they may be transiently exposed by dynamic fluctuations. Their study used a suite of molecular dynamics and enhanced sampling techniques to explore this possibility.

The cover image of the April 16 issue of Biophysical Journal shows a snapshot from one of the study’s molecular dynamics trajectories in the foreground on a generative artificial intelligence–designed background. Large-scale motions in the spike protein that open it up are investigated and expose the cryptic, conserved region mentioned above. The exposure of such a region could make it vulnerable to therapeutic interventions. The spike protein contains sugar molecules on its surface that act as an immunological shield, and the authors find that these also tend to hinder the spike from undertaking these opening motions. Nonetheless, transient opening may be sufficient for nanobodies and some antibodies to bind to the conserved region.

Vaccines typically use the entire spike protein as immunogens, so they tend to raise antibodies primarily to mutable, non-conserved regions. It would be of interest to design an immunogen by using the conserved region of the spike, which might be accessible at least transiently. To this end, similar analyses by the authors show that the conserved domain in isolation does not undergo the large conformational extensions seen in vivo during viral entry. This finding has favorable consequences for the design of an effective immunogen by using this conserved region. 

— Pranav Garg, Shawn C. C. Hsueh, and Steven S. Plotkin