Abstract 1574 Structural insights into the dynamics of bat coronavirus spike glycoprotein

Coronaviruses (CoVs) have a long-standing history as potential threats to human health. Betacoronaviruses (a class of coronaviruses) can be subdivided into sarbecoviruses, merbecoviruses, embecoviruses and nobecoviruses. SHC014-CoV, a sarbecovirus, was sequenced from horseshoe bats in Yunnan Province, China. Previous studies have shown that SHC014-CoV can infect human airway cells. In this light, the emergence of SARS-CoV-2, resulting in the coronavirus disease 19 (COVID-19) pandemic, has highlighted the potential for a possible spill-over of SHC014-CoV from bats to humans. Identifying the biophysical modifications that may unlock SHC014-CoV bat-to-human spillover could support pandemic preparedness efforts. Currently, there is no known structure of SHC014 spike protein which is a major setback towards attaining fundamental knowledge of this virus. In this study, our collaborators have used cryo-electron microscopy to resolve the first structure of the SHC014-CoV spike. In the Amaro Lab, we have then used various homology modeling tools, including AlphaFold, I-Tasser, SwissModel, and Chimera Modeller, to fill in missing loops, resulting in construction of the full-length (fl) SHC014 spike wildtype model. We then modeled a glycoprofile similar to that seen in the human SARS-CoV-2 spike while adding glycan N370 that is present on SHC014-CoV but not in human SARS-CoV-2. Results presented in this presentation will include a discussion and comparison of modeling methods used and their ability to reliably capture structure of unresolved flexible loops. We also discuss results from molecular dynamics simulations highlighting the interplay between protein and glycan structure.