Differential thermodynamics and kinetics of prefusion spike proteins of SARS-CoV-1 and 2.

by Kumar, Vivek Govind; Ogden, Dylan; Isu, Ugochi; Polasa, Adithya; Losey, James; Moradi, Mahmoud

Within the last two decades, severe acute respiratory syndrome 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 SARS-CoV-2 is the S gene that encodes the spike protein, which mediates a crucial step in the infection, i.e., host cell recognition and viral entry. Recent structural and functional studies have shed light on the differential binding behavior of the SARS-CoV-1 and SARS-CoV-2 spike proteins. In particular, cryogenic electron microscopy studies show that angiotensin converting enzyme 2 (ACE2) binding is preceded by a large-scale conformational change in the spike protein to expose the receptor binding domain (RBD) to its binding partner. Unfortunately, these studies do not provide detailed information on the dynamics of this activation process. Here, we have used an extensive set of unbiased and biased microsecond-level all-atom mol. dynamics (MD) simulations of SARS-CoV-1 and SARS-CoV-2 spike protein ectodomains in their prefusion state to det. the differential behavior of spike protein activation in the two viruses. Our results indicate that the two proteins are assocd. with substantially different thermodn. and kinetic properties. The active form of the SARS-CoV-2 spike protein is considerably more stable than the active SARS-CoV-1 spike protein and the energy barrier between the active and inactive states is significantly higher for the SARS-CoV-2 spike protein, indicating a slower kinetics. Employing state-of-the-art path-finding algorithms, we also observe that the conformational transition pathway assocd. with the activation process is drastically different for the two proteins. Based on these results we postulate that the effective binding process should not be reduced to the binding of ACE2 receptor to the RBD region, but the activation process, which involves not only the RBD but also the rest of the protein, should also be considered as an important part of the binding process. This hypothesis has important implications in spike-based vaccine and therapeutic development as the activation/deactivation process can be targeted as a way of inhibiting the binding process.