Physical epistatic landscape of antibody binding affinity

TL;DR

This study maps the antibody-antigen affinity landscape, revealing significant epistasis that influences binding and mutational pathways, with implications for vaccine development.

Contribution

Developed a null model for noninteracting mutations and characterized the physical epistatic landscape of antibody binding affinity using Tite-Seq data.

Findings

Affinity as binding free energy minimizes epistasis

Significant beneficial and negative epistasis observed

Epistasis expands mutational accessibility and sequence degeneracy

Abstract

Affinity maturation produces antibodies that bind antigens with high specificity by accumulating mutations in the antibody sequence. Mapping out the antibody-antigen affinity landscape can give us insight into the accessible paths during this rapid evolutionary process. By developing a carefully controlled null model for noninteracting mutations, we characterized epistasis in affinity measurements of a large library of antibody variants obtained by Tite-Seq, a recently introduced Deep Mutational Scan method yielding physical values of the binding constant. We show that representing affinity as the binding free energy minimizes epistasis. Yet, we find that epistatically interacting sites contribute substantially to binding. In addition to negative epistasis, we report a large amount of beneficial epistasis, enlarging the space of high-affinity antibodies as well as their mutational accessibility. These properties suggest that the degeneracy of antibody sequences that can bind a given antigen is enhanced by epistasis - an important property for vaccine design.