Local and global anatomy of antibody‐protein antigen recognition

Abstract

Deciphering antibody-protein antigen recognition is of fundamental and practical significance. We constructed an antibody structural dataset, partitioned it into human and murine subgroups, and compared it with nonantibody protein-protein complexes. We investigated the physicochemical properties of regions on and away from the antibody-antigen interfaces, including net charge, overall antibody charge distributions, and their potential role in antigen interaction. We observed that amino acid preference in antibody-protein antigen recognition is entropy driven, with residues having low side-chain entropy appearing to compensate for the high backbone entropy in interaction with protein antigens. Antibodies prefer charged and polar antigen residues and bridging water molecules. They also prefer positive net charge, presumably to promote interaction with negatively charged protein antigens, which are common in proteomes. Antibody-antigen interfaces have large percentages of Tyr, Ser, and Asp, but little Lys. Electrostatic and hydrophobic interactions in the Ag binding sites might be coupled with Fab domains through organized charge and residue distributions away from the binding interfaces. Here we describe some features of antibody-antigen interfaces and of Fab domains as compared with nonantibody protein-protein interactions. The distributions of interface residues in human and murine antibodies do not differ significantly. Overall, our results provide not only a local but also a global anatomy of antibody structures.

A compact vocabulary of paratope-epitope interactions enables predictability of antibody-antigen binding

“…Indeed, we found only minor differences in paratope motif spaces used by mouse and humans (>50% overlap, Suppl Fig. 4C, 14) and it was recently shown that neither CDR/FR length nor the distribution of interface residues in human and murine antibodies differ substantially (Collis et al, 2003;Henry and MacKenzie, 2018;Wang et al, 2018).…”

“…Over the last decades, the increasing amount of antibody-antigen crystal structures has enabled the first quantitative insight into the physicochemical features of antibody-antigen interaction (Benjamin et al, 1984;Berzofsky, 1985;Burkovitz et al, 2013;Dalkas et al, 2014;Lawrence and Colman, 1993;MacCallum et al, 1996;Ofran et al, 2008;Peng et al, 2014;Raghunathan et al, 2012;Sela-Culang et al, 2013;Sivalingam and Shepherd, 2012). For example, it has been observed repeatedly that paratopes localize mostly, but not exclusively, to CDRs (Kunik et al, 2012a), and that certain amino acids are preferentially enriched or depleted in the antibody binding regions (Mian et al, 1991;Nguyen et al, 2017;Ramaraj et al, 2012;Sela-Culang et al, 2013;Wang et al, 2018). For epitopes, several analyses have shown that their amino-acid composition is essentially indistinguishable from that of other surfaceexposed non-epitope residues if the corresponding antibody is not taken into account (Kringelum et al, 2013;Kunik and Ofran, 2013;Ponomarenko and Bourne, 2007).…”

High Molecular Weight Chitosan-Complexed RNA Nanoadjuvant for Effective Cancer Immunotherapy

“…The positive charge of RA/CTS polyplexes may support the interaction between the polyplex and tumor antigen. Because most human antigens possess a negative charge [21,22], RA/CTS polyplexes could potentially interact with other tumor antigen proteins in future applications.…”

In Silico Methods in Antibody Design

“…The interface residues with low side-chain entropy are selected to compensate for the high backbone entropy when interacting with protein antigens Positively charged and polar antigen residues and bridging water molecules have a higher possibility of being selected on the antibody-protein antigen interface. Tyr, Ser, and Asp but few Lys are selected on the antibody-antigen interfaces [44]. K. Tharakaraman et al generated a similar matrix using the available crystal structure.…”