SageTCR: a structure-based model integrating residue- and atom-level representations for enhanced TCR-pMHC binding prediction.

T-cell receptors (TCRs) recognize peptide-MHC (pMHC) complexes through intricate structural interactions, which is a core component of adaptive immunity. However, the diverse and cross-reactive nature of TCRs poses great challenges for accurate prediction of TCR-epitope interactions, hampering the advancement and broad application of TCR-related therapies. Here, we present SageTCR, a bi-level graph neural network (GNN) framework that leverages structural data to predict TCR-pMHC binding possibilities. Harnessing the pretrained language models, SageTCR encodes detailed structural arrangement at both residue-level and atomic-level and effectively integrates the bimodal representations via attention mechanisms. To tackle the deficiency of experimental structures, we explore comprehensive data augmentation strategies to enrich the training and increase the generalizability while concurrently preserving the characteristic TCR-pMHC diagonal binding mode. SageTCR demonstrates superior performance compared to six methods with different deep learning architectures. Furthermore, SageTCR offers the interpretability by identifying and focusing on the conformational features of pivotal contact residues on the interface, which can provide valuable insights for TCR engineering and immunotherapy design.