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

SARS-CoV-2
is a health threat with dire socioeconomical consequences.
As the crucial mediator of infection, the viral glycosylated spike
protein (S) has attracted the most attention and is at the center
of efforts to develop therapeutics and diagnostics. Herein, we use
an original decomposition approach to identify energetically uncoupled
substructures as antibody binding sites on the fully glycosylated
S. Crucially, all that is required are unbiased MD simulations; no
prior knowledge of binding properties or ad hoc parameter combinations
is needed. Our results are validated by experimentally confirmed structures
of S in complex with anti- or nanobodies. We identify poorly coupled
subdomains that are poised to host (several) epitopes and potentially
involved in large functional conformational transitions. Moreover,
we detect two distinct behaviors for glycans: those with stronger
energetic coupling are structurally relevant and protect underlying
peptidic epitopes, and those with weaker coupling could themselves
be prone to antibody recognition.