Atomic-level characterization of the conformational transition pathways in SARS-CoV-1 and SARS-CoV-2 spike proteins

Severe acute respiratory syndrome (SARS) coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2) derive transmissibility from spike protein activation in the receptor binding domain (RBD) and binding to the host cell angiotensin converting enzyme 2 (ACE2). However, the mechanistic details that describe the large-scale conformational changes associated with spike protein activation or deactivation are still somewhat unknown. Here, we have employed an extensive set of nonequilibrium all-atom molecular dynamics (MD) simulations, utilizing a novel protocol, for the SARS-CoV-1 (CoV-1) and SARS-CoV-2 (CoV-2) prefusion spike proteins in order to characterize the conformational pathways associated with the active-to-inactive transition. Our results indicate that both CoV-1 and CoV-2 spike proteins undergo conformational transitions along pathways unique to each protein. We have identified a number of key residues that form various inter-domain saltbridges, suggesting a multi-stage conformational change along the pathways. We have also constructed the free energy profiles along the transition pathways for both CoV-1 and CoV-2 spike proteins. The CoV-2 spike protein must overcome larger free energy barriers to undergo conformational changes towards protein activation or deactivation, when compared to CoV-1.