J Chem Inf Model. 2023 Nov 22. doi: 10.1021/acs.jcim.3c01293. Online ahead of print.
Identifying the interactions between T-cell receptor (TCRs) and human antigens is a crucial step in developing new vaccines, diagnostics, and immunotherapy. Current methods primarily focus on learning binding patterns from known TCR binding repertoires by using sequence information alone without considering the binding specificity of new antigens or exogenous peptides that have not appeared in the training set. Furthermore, the spatial structure of antigens plays a critical role in immune studies and immunotherapy, which should be addressed properly in the identification of interacting TCR-antigen pairs. In this study, we introduced a novel deep learning framework based on generative graph structures, GGNpTCR, for predicting interactions between TCR and peptides from sequence information. Results of real data analysis indicate that our model achieved excellent prediction for new antigens unseen in the training data set, making significant improvements compared to existing methods. We also applied the model to a large COVID-19 data set with no antigens in the training data set, and the improvement was also significant. Furthermore, through incorporation of additional supervised mechanisms, GGNpTCR demonstrated the ability to precisely forecast the locations of peptide-TCR interactions within 3D configurations. This enhancement substantially improved the model’s interpretability. In summary, based on the performance on multiple data sets, GGNpTCR has made significant progress in terms of performance, universality, and interpretability.