Identification of discontinuous antigenic determinants on proteins based on shape complementarities

Diverse procedures for identifying antigenic determinants on proteins have been developed, including experimental as well as computational approaches. However, most of these techniques focus on continuous epitopes, whereas fast and reliable identification and verification of discontinuous epitopes remains barely amenable. In this paper, we describe a computational workflow for the detection of discontinuous epitopes on proteins. The workflow uses a given protein 3D structure as input, and combines a per residue solvent accessibility constraint with epitope to paratope shape complementarity measures and binding energies for assigning antigenic determinants in the conformational context. We have developed the procedure on a given set of 26 antigen-antibody complexes with a known structure, and have further expanded the available paratope shapes by generating a virtual paratope library in order to improve the screening for candidate residues constituting discontinuous epitopes. Applying the workflow on the 26 given antigens with known discontinuous epitopes resulted in the correct identification of the spatial proximity of 12 antigen-antibody interaction sites. Combining solvent accessibility, shape complementarity and binding energies towards the identification of discontinuous epitopes clearly outperforms approaches solely considering accessibility and residue distance constraints.