A unified deep framework for peptide–major histocompatibility complex–T cell receptor binding prediction

Antigen peptides that are presented by a major histocompatibility complex (MHC) and recognized by a T cell receptor (TCR) have an essential role in immunotherapy. Although substantial progress has been made in predicting MHC presentation, accurately predicting the binding interactions between antigen peptides, MHCs and TCRs remains a major computational challenge. In this paper, we propose a unified deep framework (called UniPMT) for peptide, MHC and TCR binding prediction to predict the binding between the peptide and the CDR3 of TCR β in general, presented by class I MHCs. UniPMT is comprehensively validated by a series of experiments and achieved state-of-the-art performance in the peptide–MHC–TCR, peptide–MHC and peptide–TCR binding prediction tasks with up to 15% improvements in area under the precision–recall curve taking the peptide–MHC–TCR binding prediction task as an example. In practical applications, UniPMT shows strong predictive power, correlates well with T cell clonal expansion and outperforms existing methods in neoantigen-specific binding prediction with up to 17.62% improvements in area under the precision–recall curve on experimentally validated datasets. Moreover, UniPMT provides interpretable insights into the identification of key binding sites and the quantification of peptide–MHC–TCR binding probabilities. In summary, UniPMT shows great potential to serve as a useful tool for antigen peptide discovery, disease immunotherapy and neoantigen vaccine design. UniPMT, a multitask learning model, is presented, which integrates three key biological relationships into a unified framework for accurate peptide–MHC–TCR binding prediction.