Conformational free energy landscape of prefusion spike protein in SARS-CoV-1 and 2.
by Moradi, Mahmoud; Kumar, Vivek Govind; Ogden, Dylan S.; Isu, Ugochi H.; Polasa, Adithya; Losey, James; Derakhshani, Mortaza
Within the last two decades, severe acute respiratory syndrome (SARS) coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2) have caused two major outbreaks. For reasons yet to be fully understood the COVID-19 outbreak caused by SARS-CoV-2 has been significantly more widespread than the 2003 SARS epidemic caused by SARS-CoV-1, despite striking similarities between the two viruses. One of the most variable genes differentiating SARS-CoV-1 and 2 is the S gene that encodes the spike protein. This protein, which binds to the host cell angiotensin converting enzyme 2 (ACE2) in both SARS-CoV-1 and 2, has been implied to be a potential source of their differential transmissibility. However, the mechanistic details of spike protein binding to ACE2 remain elusive at the mol. level. Here, we have used an extensive set of microsecond-level all-atom mol. dynamics (MD) simulations of SARS-CoV-1 and 2 spike proteins in their pre-fusion state to det. the differential dynamic behavior of spike protein structure of the two viruses. We have performed equil. and nonequil. (targeted MD) as well as path-finding (string method) and enhanced sampling (umbrella sampling) simulations of both glycosylated and non-glycosylated prefusion spike proteins of SARS-CoV-1 and 2 to characterize conformational free energy landscapes of these proteins. Our results indicate that both the active and inactive forms of the SARS-CoV-2 spike protein are more stable than their counterpart in SARS-CoV-1 in both glycosylated and non-glycosylated forms of the two proteins. This differential behavior is due to a difference in the energy barrier assocd. with the activation/deactivation process in the two viruses. We have also identified a previously unknown inactive state of SARS-CoV-1 spike protein, where the receptor binding domain (RBD) and the N-terminal domain (NTD) of the protein interact. Our results suggest that not only the RBD but also other domains, in particular NTD, could play a crucial role in the differential binding behavior of SARS-CoV-1 and 2 spike proteins.