Towards Understanding the Drivers of Antibody-Antigen Binding

Abstract 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 apo 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 highlights that at least in most cases antibodies drive antibody-antigen interactions. Statement of Significance Antibodies represent an important and expanding class of therapeutics for a range of diseases including infectious diseases, cancers, and autoimmune disorders. Enhancing our fundamental understanding of what drives antibody-antigen interactions is critical to our enhancing our ability to modulate these interactions. This work presents a systematic, physics-based study of antibody-antigen interfaces, and identifies key drivers of binding.