Essential Dynamics That Drive Sars-Cov-2 Spike Conformational Changes

The ongoing COVID-19 pandemic caused by the SARS-CoV-2 virus has prompted the need for rapid development of effective vaccines to attenuate this global emergency. The Spike glycoprotein present on the surface of this virus is known to elicit immune response and has been a prime candidate for vaccine design. This trimeric protein plays a critical role in infection where its Receptor Binding Domain (RBD) moves upwards from the rest of protein making it free to bind with the host ACE2 receptor. This is followed by S1-S2 subdomain disengagement and cell entry. Structural understanding of such inter-domain motions is important for obtaining an effective molecular handle over this protein, and in turn, exploiting it towards improved immunogen development. We performed large-scale molecular dynamics simulations of the soluble form of the Spike in both ‘down’ and ‘up’ conformations of the RBD, and employed Principal Component Analysis (PCA) of the inter-residue correlated fluctuations to extract major collective modes that dominate the functional dynamics. We observe that there is significant influence of coupled dynamics connecting the RBD, the N-terminal Domain (NTD) and the S2 region that can drive RBD transitions. Moreover, both RBD and NTD sample disparate rotational space between the Up- and Down-RBD conformations, that can affect antibody interactions. Since the Spike is densely glycosylated, simulations were also performed for the dominant Spike glycoform to elucidate the effect of glycans on these essential dynamics. Our results further provide a mechanistic rationale for the allosteric modulations that distinguish the predominant D614G viral Spike form which has been shown to have enhanced infectivity and RBD-up probability.