Free Energy Landscapes from SARS-CoV-2 Spike Glycoprotein Simulations Suggest that RBD Opening Can Be Modulated via Interactions in an Allosteric Pocket

Abstract

The SARS-CoV-2 coronavirus is an enveloped, positive-sense single-stranded RNA virus that is responsible for the COVID-19 pandemic. The spike is a class I viral fusion glycoprotein that extends from the viral surface and is responsible for viral entry into the host cell and is the primary target of neutralizing antibodies. The receptor binding domain (RBD) of the spike samples multiple conformations in a compromise between evading immune recognition and searching for the host-cell surface receptor. Using atomistic simulations of the glycosylated wild-type spike in the closed and 1-up RBD conformations, we map the free energy landscape for RBD opening and identify interactions in an allosteric pocket that influence RBD dynamics. The results provide an explanation for experimental observation of increased antibody binding for a clinical variant with a substitution in this pocket. Our results also suggest the possibility of allosteric targeting of the RBD equilibrium to favor open states via binding of small molecules to the hinge pocket. In addition to potential value as experimental probes to quantify RBD conformational heterogeneity, small molecules that modulate the RBD equilibrium could help explore the relationship between RBD opening and S1 shedding.

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

“…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 …”

“…As a caveat, it is worth pointing out here the fact that antibodies can bind to conformations of the spike protein that are different from the ones sampled here. Indeed, work by Casalino et al, 50 Zimmerman et al, 53 and by Fallon et al 59 show that the protein can undergo dramatic structural changes. In our simulations, despite running 4 ms of all-atom MD simulation for each system, we could not observe such changes, if not in their initial stages.…”

Plant-Produced Glycosylated and In Vivo Deglycosylated Receptor Binding Domain Proteins of SARS-CoV-2 Induce Potent Neutralizing Responses in Mice

“…It was shown that the RBD alternates between two distinct conformational states relative to the remainder of the spike: “open” and “closed” [ 23 , 24 , 25 ]. A conserved allosteric pocket adjacent to a hinge region was recently identified as critical for the RBD opening and closing motion [ 26 ]. The S protein of SARS-CoV-2 is a cysteine-rich protein, and nine cysteine residues are found in the RBD, eight of which are involved in forming four pairs of disulfide bridges [ 22 ].…”

The supramolecular organization of SARS-CoV and SARS-CoV-2 virions revealed by coarse-grained models of intact virus envelopes

“…The S protein has a dense coating of glycans, to evade the host immune system. Atomistic simulations also demonstrated that the glycans play an essential role in modulating the conformational transitions of the S protein (18,33,34,49,52). Our models in this study did not include glycans.…”

“…New structures of SARS-CoV-2 proteins have been obtained by cryo-electron microscopy (cryo-EM) nearly weekly (16)(17)(18)(19)(20)(21). Computational approaches have also been used for structural prediction of unresolved sections (22), molecular dockings of different drug molecules on virus proteins (23)(24)(25)(26), and free energy calculations of the S-ACE2 binding process (27)(28)(29)(30)(31)(32) and the down-up transition of the receptor binding domain (RBD) (33,34). The larger scale spatio-temporal processes, such as virion assembly, virus architecture, fusion, and budding, are still poorly understood, and remain challenging for experimental techniques as well as all-atom molecular dynamics (MD) simulations (35).…”