Intrinsically Disordered Regions Function as a Cervical Collar to Remotely Regulate the Nodding Dynamics of SARS-CoV-2 Prefusion Spike Heads.

Abstract

The SARS-CoV-2 prefusion spike heads (receptor binding domains, RBDs) frequently nod down and up to interact with host cell receptors. As the spike protein is a trimeric unit of significant size, to understand its large-scale structural dynamics associated with the nodding mechanism and the mutational impact on the same, we develop a topological symmetry-information-loaded coarse-grained structure-based model of a spike trimer using recent cryo-EM structural data. Our study reveals the control of two distant intrinsically disordered regions (IDRs), namely, 630 and FPPR loops, over the nodding dynamics of spike heads. We find that the order-disorder transition of IDRs becomes more evident in the variants of concern (VOCs) that are associated with the characteristic mutation, D614G, in the proximity of these IDRs. In some VOCs, the two other mutations A570D and S982A also show an integral effect. The driver mutation D614G instigates a salt-bridge disruption, altering the order-disorder dynamics of both 630 and FPPR loops and their interaction with the C-terminal domains (CTD1/CTD2). This altered connectivity in these mutants allows the two IDRs to act collectively as a "cervical collar" for the RBD, supporting various spike head postures, consistent with cryo-EM results available for specific cases. The IDRs' control over the spike structure and dynamics presents an exciting opportunity where they can be targeted as remote operational switches to artificially maneuver the nod for effective therapeutic interventions.