Distinct Mechanisms in receptor binding domain activation in the glycoprotein spikes of SARS-CoV-1 and SARS-CoV-2

We seek an atomic-level rationale for the observation that SARS-CoV-2 is more transmissible than SARS-CoV-1 by hypothesizing that the former has a lower activation energy barrier in its S glycoprotein spike between apo and receptor-bound states than the latter. We will conduct all-atom MD simulations with umbrella sampling and weighted-histogram analysis to construct free-energy landscapes for S activation for the SARS-CoV-1 and SARS-CoV-2 spike glycoprotein ectodomains based on recent cryo-EM structures. We will also model unique constructs aimed at pinpointing reasons for differences in activation energy. If successful, our project will establish a platform to investigate effects of mutations and potential inhibitors on spike activation.