While my own research focuses mainly on what happens in an antibody before it binds its antigen, I recently came across a paper by Akbar et al [1] that examines antibody-antigen interactions using an elegant approach to identify a set of structural motifs that antibodies use to interact with their epitopes. Since I am interested in emergent properties that arise when a sequence is mapped onto an antibody structure, this paper was very exciting. I will also shamelessly admit that I’m a sucker for a pretty figure and this paper has many! Regardless, on to the findings!

1. Short interaction motifs enable comparison of unrelated paratopes and epitopes: By splitting interacting regions up into short motifs, the authors show that unrelated interacting surfaces can be compared since interacting regions of a protein can be up to hundreds of residues apart when mapped on linear sequences. To get around this, the authors instead use short motifs of the form XXX where X is an interacting amino acid (or interacting residues flanking gap residues, XNX, where N is the number of non-interacting residues).
2. The identified interaction motifs are part of a compact set unique to antibodies: The authors show that only a small subset of all possible such motifs are employed by antibodies, indicating that a compact dictionary of motifs can be used combinatorially to bind virtually any epitope. Further, the authors compared such antibody motifs to general protein-protein interaction motifs using the same method, and found distinct differences, suggesting a unique set of interaction motifs with immunological function.
3. Lastly, the authors demonstrate learnability of these motifs. Given a paratope interaction motif, the authors show that the corresponding epitope motif can be predicted and vice versa. Perhaps the most exciting result reported, this shows that these short motifs provide an avenue for de novo epitope and antibody design.

The study has two main takeaways. One is that antibodies use combinations of unique structural motifs to create a nearly unlimited array of paratopes while the second takeaway is that an understanding of how these combinations are generated and how individual motifs drive overall interaction behaviour can allow de novo design of both antibodies as well as epitopes.

References:

[1] Akbar, R., Robert, P. A., Pavlović, M., Jeliazkov, J. R., Snapkov, I., Slabodkin, A., Weber, C. R., Scheffer, L., Miho, E., Haff, I. H., Haug, D. T. T., Lund-Johansen, F., Safonova, Y., Sandve, G. K., & Greiff, V. (2021). A compact vocabulary of paratope-epitope interactions enables predictability of antibody-antigen binding. Cell Reports, 34(11). https://doi.org/10.1016/j.celrep.2021.108856