Abstract
B-cell epitope prediction for antipeptide antibody responses enables peptide-based vaccine design and related translational applications. This entails estimating epitope-paratope binding free-energy changes from antigen sequence; but attempts to do so assuming uniform epitope length (e.g., of hexapeptide sequences, each spanning a typical paratope diameter when fully extended) have neglected empirically established variation in epitope length. Hence, a more physicochemically realistic approach is developed herein by analogy between epitope-paratope binding and protein folding modeled as polymer collapse, treating paratope structure implicitly. Epitope-paratope binding is thus conceptually resolved into processes of epitope compaction, collapse and contact, with epitope collapse presenting the main entropic barrier limiting epitope length among non-polyproline sequences. Such analysis applied to representative known peptide immunogens predicts immunodominant epitopes with length from six to 12 (median of nine) residues, consistent with known paratope-bound structures of flexibly disordered epitopes. However, weak correlation was found between predicted association constants (calculated from estimated free-energy changes for binding of predicted immunodominant epitopes by complementary paratopes) and their experimentally determined counterparts, possibly reflecting multiple factors (e.g., variable extent of affinity maturation, avidity gain due to epitope-sequence repeats, and structural differences between immunogens and corresponding assay antigens). This work serves to support further advancement of B-cell epitope prediction.
Published Version
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