TCR-ESM: Employing protein language embeddings to predict TCR-peptide-MHC binding

Cognate target identification for T-cell receptors (TCRs) is a significant barrier in T-cell therapy development, which may be overcome by accurately predicting TCR interaction with peptide-bound major histocompatibility complex (pMHC). In this study, we have employed peptide embeddings learned from a large protein language model- Evolutionary Scale Modeling (ESM), to predict TCR-pMHC binding. The TCR-ESM model presented outperforms existing predictors. The complementarity-determining region 3 (CDR3) of the hypervariable TCR is located at the center of the paratope and plays a crucial role in peptide recognition. TCR-ESM trained on paired TCR data with both CDR3 alpha and CDR3 beta chain information performs significantly better than those trained on data with only CDR3 beta, suggesting that both TCR chains contribute to specificity, the relative importance however depends on the specific peptide-MHC targeted. The study illuminates the importance of MHC information in TCR-peptide binding which remained inconclusive so far and was thought dependent on the dataset characteristics. TCR-ESM outperforms existing approaches on external datasets, suggesting generalizability. Overall, the potential of deep learning for predicting TCR-pMHC interactions and improving the understanding of factors driving TCR specificity are highlighted. The prediction model is available at http://tcresm.dhanjal-lab.iiitd.edu. in/ as an online tool.