Predictability of antigen binding based on short motifs in the antibody CDRH3

Adaptive immune receptors, such as antibodies and T-cell receptors, recognize foreign threats with exquisite specificity. A major challenge in adaptive immunology is discovering the rules governing immune receptor-antigen binding in order to predict the antigen binding status of previously unseen immune receptors. Many studies assume that the antigen binding status of an immune receptor may be determined by the presence of a short motif in the complementarity determining region 3 (CDR3), disregarding other amino acids. To test this assumption, we present a method to discover short motifs which show high precision in predicting antigen binding and generalize well to unseen simulated and experimental data. Our analysis of a mutagenesis-based antibody dataset reveals 11 336 position-specific, mostly gapped motifs of 3-5 amino acids that retain high precision on independently generated experimental data. Using a subset of only 178 motifs, a simple classifier was made that on the independently generated dataset outperformed a deep learning model proposed specifically for such datasets. In conclusion, our findings support the notion that for some antibodies, antigen binding may be largely determined by a short CDR3 motif. As more experimental data emerge, our methodology could serve as a foundation for in-depth investigations into antigen binding signals.