Receptor binding may directly activate the fusion machinery in coronavirus spike glycoproteins

Abstract

SARS-CoV-2, the causative agent of the COVID-19 pandemic, is an enveloped RNA virus. Trimeric spike glycoproteins extend outward from the virion; these class I viral membrane fusion proteins mediate entry of the virus into a host cell and are the dominant antigen for immune response. Cryo-EM studies have generated a large number of structures for the spike either alone, or bound to the cognate receptor ACE2 or antibodies, with the three receptor binding domains (RBDs) seen closed, open, or in various combinations. Binding to ACE2 requires an open RBD, and is believed to trigger the series of dramatic conformational changes in the spike that lead to the shedding of the S1 subunit and transition of the spring-loaded S2 subunit to the experimentally observed post-fusion structure. The steps following ACE2 binding are poorly understood despite extensive characterization of the spike through X-ray, cryo-EM, and computation. Here, we use all-atom simulations, guided by analysis of 81 existing experimental structures, to develop a model for the structural and energetic coupling that connects receptor binding to activation of the membrane fusion machinery.

SARS-CoV-2 Spike Protein Mutations and Escape from Antibodies: A Computational Model of Epitope Loss in Variants of Concern

“…In this work, we analyzed full-length models of 7 trimeric glycosylated SARS-CoV-2 S protein variants, derived from the prefusion conformation of the Cryo-EM structure 6VSB, 11 in which the receptor binding domain of chain A (RBD-A) is in an "up" conformation, exposed to interaction with host cell receptors and potential targeting by Abs. The data from our energetic analyses can be aptly integrated in the characterization of the properties of S and other SARS-CoV-2 proteins from long scale simulations, such as those recently presented by Zimmerman et al, 53 Casalino et al, 50 Spinello et al, 54,55 Oliveira et al, 56 Shoemark et al, 57 Wang et al, 58 and Fallon. 59 Our MLCE analysis of the full-length trimers correctly identifies a number of epitopes in the RBD that have been previously experimentally characterized.…”

SARS-CoV-2 spike opening dynamics and energetics reveal the individual roles of glycans and their collective impact

“…42 In fact, Gobeil et al 12 report that for the S-protein construct with the furin site removed, the presence of the prolines produces structures, ACE2 binding, thermal stability, and antibody binding that are remarkably similar to the WT K986/V987 pair. Of note, recent simulations by Wang et al 43 exploring the transition from the pre-to post-fusion states have shown that while the WT sequence at 986/987 has a tendency to become helical, replacement with prolines disrupts the formation of this secondary structure.…”

“…The presence of the prolines, residues known to break/kink α-helices, inhibits the formation of the long α-helix characteristic of the post-fusion conformation 49 . Of note, recent simulations by Wang et al 50 exploring the transition from the pre-to post-fusion states have shown that while the WT sequence at 986/987 has a tendency to become helical, replacement with prolines disrupts the formation of this secondary structure.…”