Distinct Structural Flexibility within SARS-CoV-2 Spike Protein Reveals Potential Therapeutic Targets

Serena H. Chen; M. Todd Young; John Gounley; Christopher Stanley; Debsindhu Bhowmik

The exposed surface in the protomer may provide new targets for therapeutic action. Therefore, we further explored the structural flexibility of the SARS-CoV-2 S protein. We compared the structures between the protomer and trimer to investigate whether the large structural arrangement of the domains in the protomer is affected by the trimeric state. We found that domain organization is stabilized by trimerization. Unlike the protomer, the three domains are closely arranged in the trimer (Figs. 3 A-B and S4). In addition to their interdomain distances, the differences in structural flexibility between the protomer and trimer is captured in solventaccessible surface area (SASA) values (Fig. 3 C) . The SASA values of the protomer and one chain of the trimer are 532 ± 10 nm 2 and 450 ± 8 nm 2 , respectively. The difference in these values largely comes from their S2 domains, which have the values of 228 ± 7 nm 2 and 170 ± 5 nm 2 , respectively. Again, we applied a CVAE to encode the 10,000 protomer and trimer structures into 3-D latent spaces. We found two individual clusters, one corresponding to the protomer and the other to the trimer, suggesting that the structural features of the two oligomeric states embedded in the latent spaces are different (Fig. 3 D-G) .