Toward understanding the drivers of antibody-antigen binding

Antibody therapeutics are capable of binding to target antigens with a high degree of specificity and affinity. Gaining an understanding of how antibody-antigen interactions are governed can provide valuable insights that may assist with rational paratope design and epitope prediction. In this work, we apply the FTMap algorithm to systematically characterize binding hot spots-regions on a protein surface that contribute disproportionately to molecular recognition-to a set of 50 antibody-antigen complexes. From our analysis, we find that interface hot spots are typically concentrated on the paratope (antibody side) of the interface, indicating that paratopes typically function as hot-spot-rich environments in which the antigen can bind. Additionally, we observe that hot spot formation on both sides of the interface is particularly enriched by Trp and Tyr residues, underscoring the key role of aromatic side chains with some amphiphilic character in antibody design. Furthermore, we find that when strong interface hot spots are detected, they tend to persist in the unbound conformation, suggesting that there is an inherent structural stability that surrounds core interface hot spots. These findings demonstrate the utility of computational solvent mapping for analyzing protein-protein interfaces, and they highlight that, at least in most cases in our analyzed set, antibodies drive antibody-antigen interactions.