Attention-aware differential learning for predicting peptide-MHC class I binding and T cell receptor recognition

The identification of neoantigens is crucial for advancing vaccines, diagnostics, and immunotherapies. Despite this importance, a fundamental question remains: how to model the presentation of neoantigens by major histocompatibility complex class I molecules and the recognition of the peptide-MHC-I (pMHC-I) complex by T cell receptors (TCRs). Accurate prediction of pMHC-I binding and TCR recognition remains a significant computational challenge in immunology due to intricate binding motifs and the long-tail distribution of known binding pairs in public databases. Here, we propose an attention-aware framework comprising TranspMHC for pMHC-I binding prediction and TransTCR for TCR-pMHC-I recognition prediction. Leveraging the attention mechanism, TranspMHC surpasses existing algorithms on independent datasets at both pan-specific and allele-specific levels. For TCR-pMHC-I recognition, TransTCR incorporates transfer learning and a differential learning strategy, demonstrating superior performance and enhanced generalization on independent datasets compared to existing methods. Furthermore, we identify key amino acids associated with binding motifs of peptides and TCRs that facilitate pMHC-I and TCR-pMHC-I binding, indicating the potential interpretability of our proposed framework.