Structure-Directed Pan-Specific T-Cell Receptor–Peptide-Major Histocompatibility Complex Interaction Prediction

T-cell receptors (TCRs) play a pivotal role in the adaptive immune system, and understanding their antigen recognition mechanism remains a critical area of research. With the increasing availability of binding and interaction data between TCRs and peptide-major histocompatibility complexes (pMHCs), data-driven computational methods are emerging as powerful tools with significant potential for advancement. In this study, we collected and curated comprehensive sequence and structure data sets of TCRs from human CD8+ T-cells and cognate epitopes presented by MHC class I molecules. We developed two innovative computational frameworks: SG-TPMI, a lightweight, extensible, and structure-guided model for predicting TCR-pMHC binding specificity, and Seq/Struct-TCS, a pair of models (sequence-based and structure-based) for predicting contact sites within TCR-pMHC complexes. Notably, we directly integrated MHC-I alpha helices (or pseudosequences) and structural information on the protein complex into the prediction models. Our comprehensive modeling approach enabled quantitative investigations of TCR-pMHC interaction mechanisms, empowering SG-TPMI and Struct-TCS to achieve performances comparable to those of state-of-the-art methods. Furthermore, our results highlight the necessity of CDR1 and CDR2 loops as well as MHC restriction in pan-specific TCR-pMHC interaction prediction, providing new insights into TCR recognition. In summary, we not only propose SG-TPMI as an effective computational method for predicting TCR-pMHC binary interactions but also introduce the Seq/Struct-TCS design for predicting TCR interacting sites with peptide or MHC alpha helices.