Betacoronavirus SARS-CoV-2 is posing a major threat to human health and its diffusion around the world is having dire socioeconomical consequences. Thanks to the scientific community’s unprecedented efforts, the atomic structure of several viral proteins has been promptly resolved. As the crucial mediator of host cell infection, the heavily glycosylated trimeric viral Spike protein (S) has been attracting the most attention and is at the center of efforts to develop antivirals, vaccines, and diagnostic solutions.<br/>Herein, we use an original energy-decomposition approach to identify antigenic domains and antibody binding sites on the fully glycosylated S protein. Crucially, all that is required by our method are unbiased atomistic molecular dynamics simulations; no prior knowledge of binding properties or ad hoc combinations of parameters/measures extracted from simulations is needed. Our method simply relies on the analysis of energy interactions between all intra-protomer aminoacid and monosaccharide residue pairs, and cross-compares these pairwise interactions with structural information (i.e., residue-residue proximity), identifying those groups of spatially contiguous residues with poor energetic coupling to the rest of the protein as potential immunogenic regions.<br/>Our results are validated by several experimentally confirmed structures of the S protein in complex with anti- or nanobodies. We identify a number of poorly coupled subdomains, poised to host (several) epitopes, and potentially involved in large functional conformational transitions. Finally, we detect two distinct behaviors of the glycan shield: glycans with stronger energetic coupling are structurally relevant and protect underlying peptidic epitopes; those with weaker coupling could themselves be prone to antibody recognition. Predicted immunoreactive regions can be used to develop optimized antigens (recombinant subdomains, synthetic (glyco)peptidomimetics) for therapeutic applications; furthermore, the same predictive approaches could significantly increase preparedness in future pandemic outbreaks.

The answer lies in the energy: how simple atomistic molecular dynamics simulations may hold the key to epitope prediction on the fully glycosylated SARS-CoV-2 spike protein

ACS Spring Meeting 2021

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