Evolutionary aspect of spike glycoprotein's conformational dynamics.

The conformational transition of the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein from the "closed" to the "open" state is an important dynamic event influencing the infectivity of the virus. However, how accumulating mutations reshape these conformational dynamics during viral evolution remains to be clarified. In this study, we observed the motion of the RBD of fully glycosylated S protein trimers from wild type to Omicron (BA.2, BA.4&5) variants by using all-atomic molecular dynamics simulations. Our study indicates that, although a fully converged free energy landscape in all motion directions was not obtained, analysis of the molecular dynamics trajectories reveals significant differences in the RBD motional patterns among variants due to mutations. Studies have shown that specific surface mutations of the Omicron variant exhibit a strong coupling effect with glycan dynamics. This effect remodels the "glycan gate" conformation mediated by N165 and N343 glycans and subsequently regulates the motion of the RBD. These findings elucidate the molecular mechanism between viral surface mutations and glycan dynamic regulation, providing a new theoretical basis for understanding the evolutionary adaptability and biological function of the virus.