Cation–π, amino–π, π–π, and H‐bond interactions stabilize antigen–antibody interfaces

Abstract

The identification of immunogenic regions on the surface of antigens, which are able to stimulate an immune response, is a major challenge for the design of new vaccines. Computational immunology aims at predicting such regions-in particular B-cell epitopes-but is far from being reliably applicable on a large scale. To gain understanding into the factors that contribute to the antigen-antibody affinity and specificity, we perform a detailed analysis of the amino acid composition and secondary structure of antigen and antibody surfaces, and of the interactions that stabilize the complexes, in comparison with the composition and interactions observed in other heterodimeric protein interfaces. We make a distinction between linear and conformational B-cell epitopes, according to whether they consist of successive residues along the polypeptide chain or not. The antigen-antibody interfaces were shown to differ from other protein-protein interfaces by their smaller size, their secondary structure with less helices and more loops, and the interactions that stabilize them: more H-bond, cation-p, amino-p, and p-p interactions, and less hydrophobic packing; linear and conformational epitopes can clearly be distinguished. Often, chains of successive interactions, called cation/amino-p and p-p chains, are formed. The amino acid composition differs significantly between the interfaces: antigen-antibody interfaces are less aliphatic and more charged, polar and aromatic than other heterodimeric protein interfaces. Moreover, paratopes and epitopes-albeit to a lesser extent-have amino acid compositions that are distinct from general protein surfaces. This specificity holds promise for improving B-cell epitope prediction.

Structure of a TCR-Mimic Antibody with Target Predicts Pharmacogenetics

“…CDR-H2 and CDR-H3 make extensive cation-π interactions with Arg108, Arg169, and Arg170 of the HLA. The extensive chains of cation-π interactions in the ESK1-pMHC are consistent with those frequently seen in other antibody-antigen complexes [24]. …”

Structure-Function Analysis of Mammalian CYP2B Enzymes Using 7-Substituted Coumarin Derivatives as Probes: Utility of Crystal Structures and Molecular Modeling in Understanding Xenobiotic Metabolism

“…In our recent study (Shah et al, 2015), we proposed that the presence of a -Cl or -NH functional group in a ligand is an important determinant of CYP2B4 or CYP2B6 ligand binding, also shown previously with several crystal structures of protein-ligand complexes (Dougherty, 1996;Dalkas et al, 2014). Several studies in the literature have described the effect of ligands with -Cl and/or -NH functional groups on the formation of stable -p bonds with aromatic side chains via an edge-on or face-on geometry at a distance of 3.7-4.1 Å (Scrutton and Raine, 1996;Imai et al, 2008).…”

Structural and Biophysical Characterization of Human Cytochromes P450 2B6 and 2A6 Bound to Volatile Hydrocarbons: Analysis and Comparison

“…Another interesting observation from the seven structures is how the presence of a "-Cl" or "-NH" functional group influences the orientation of F206 and F297 and, consequently, the overall volume of the active site. Recent analysis of Cl-p and NH-p interactions in protein ligand complexes found in the PDB revealed the presence of two different geometries when these groups interact with aromatic rings: edge-on, where the -Cl or -NH group approaches the aromatic atoms or bonds on the periphery of the ring, or face-on, where the group interacts with the electron density at the center of the aromatic ring (Scrutton and Raine, 1996;Imai et al, 2008;Dalkas et al, 2014). The aromatic ring of the phenylalanine side chain preferred edge-on geometry for -Cl atoms, which were found predominantly in crystallographic structures at a distance range of 3.7-4.1 Å (Imai et al, 2008).…”