Development of a Polymer-Theoretic Approach to Describing Constraints on Reactions Between Antipeptide Antibodies and Intrinsically Disordered Peptide Antigens: Implications for B-Cell Epitope Prediction

B-cell epitope prediction aims to support translational applications as exemplified by peptide-based vaccine design. This entails selection of immunizing peptide sequences that tend to be intrinsically disordered and thus appropriately described within the framework of polymer theory. A fully extended hexapeptide sequence spans a typical antibody footprint; but disordered peptides are flexible rather than rigid, such that their B-cell epitopes may vary in length according to the diversity of conformations assumed upon binding by antibodies. Hence, peptides were modeled herein as worm-like chains, using an interpolated approximation of the radial probability density distribution function to estimate the probability that the ends of a peptidic sequence are separated by a distance less than or equal to a typical antibody footprint diameter. The results suggest that the epitopes are likely to be no more than 17 residues long, which is consistent with available structural data on immune complexes consisting of antipeptide antibodies bound to cognate peptide antigens. For such antigens, B-cell epitope prediction thus could proceed with initial scanning for intrinsically disordered sequences of length up to a physicochemically plausible maximum value (e.g., 17 residues), with analysis of progressively longer subsequences to identify nonredundant sets of putative epitopes (e.g., based on predicted affinity).