Structure-Regularized Interpretable TCR-Epitope Prediction

T cell receptor (TCR)-epitope binding prediction is essential for understanding adaptive immunity and developing immunotherapies. Existing sequence- and structure-based models often generalize poorly to unseen epitopes and provide limited interpretability. Furthermore, the impact of generated structures on model learning remains unclear. We present TCR-SRIM, a structure-regularized interpretable-by-design model that combines protein language model embeddings with interpretable contact prototypes to capture residue-level TCR-epitope interactions. TCR-SRIM achieves state-of-the-art predictive performance and improved interpretation quality on the TCR-XAI benchmark. Using its inherent interpretability, we further evaluate the effect of generated structures on model learning. While structures predicted by AlphaFold3, TCRModel2, and tFold-TCR yield competitive performance, they lead to less accurate interaction patterns and reduced binding-site diversity than experimentally-resolved structures. Our results highlight limitations of current structure prediction models for TCR-epitope learning and demonstrate the value of interpretable-by-design models for studying generated biological structures.

Why Does It Look There? Structured Explanations for Image Classification

Deep learning models achieve remarkable predictive performance, yet their black-box nature limits transparency and trustworthiness. Although numerous explainable artificial intelligence (XAI) methods have been proposed, they primarily provide saliency maps or concepts (i.e., unstructured interpretability). Existing approaches often rely on auxiliary models (\eg, GPT, CLIP) to describe model behavior, thereby compromising faithfulness to the original models. We propose Interpretability to Explainability (I2X), a framework that builds structured explanations directly from unstructured interpretability by quantifying progress at selected checkpoints during training using prototypes extracted from post-hoc XAI methods (e.g., GradCAM). I2X answers the question of "why does it look there" by providing a structured view of both intra- and inter-class decision making during training. Experiments on MNIST and CIFAR10 demonstrate effectiveness of I2X to reveal prototype-based inference process of various image classification models. Moreover, we demonstrate that I2X can be used to improve predictions across different model architectures and datasets: we can identify uncertain prototypes recognized by I2X and then use targeted perturbation of samples that allows fine-tuning to ultimately improve accuracy. Thus, I2X not only faithfully explains model behavior but also provides a practical approach to guide optimization toward desired targets.

TCR-EML: Explainable Model Layers for TCR-pMHC Prediction

T cell receptor (TCR) recognition of peptide-MHC (pMHC) complexes is a central component of adaptive immunity, with implications for vaccine design, cancer immunotherapy, and autoimmune disease. While recent advances in machine learning have improved prediction of TCR-pMHC binding, the most effective approaches are black-box transformer models that cannot provide a rationale for predictions. Post-hoc explanation methods can provide insight with respect to the input but do not explicitly model biochemical mechanisms (e.g. known binding regions), as in TCR-pMHC binding. ``Explain-by-design'' models (i.e., with architectural components that can be examined directly after training) have been explored in other domains, but have not been used for TCR-pMHC binding. We propose explainable model layers (TCR-EML) that can be incorporated into protein-language model backbones for TCR-pMHC modeling. Our approach uses prototype layers for amino acid residue contacts drawn from known TCR-pMHC binding mechanisms, enabling high-quality explanations for predicted TCR-pMHC binding. Experiments of our proposed method on large-scale datasets demonstrate competitive predictive accuracy and generalization, and evaluation on the TCR-XAI benchmark demonstrates improved explainability compared with existing approaches.