Benchmarking TCR-pMHC structure prediction: a unified evaluation and CDR3-based functional insights

Abstract

Interactions between T cell receptors (TCRs) and peptide-major histocompatibility complexes (pMHCs) are central to adaptive immunity. Recent advances in structure prediction tools have enabled atomic-level modeling of TCR-pMHC interactions. However, the lack of systematic evaluation forces practitioners to invest substantial resources in selecting appropriate tools. Here, we present a comprehensive benchmark of TCR-pMHC structure prediction with 70 previously unseen complexes and ten models spanning MSA-based, PLM-based, and docking-based approaches, revealing the superior modeling accuracy and docking quality of MSA-based methods, especially AlphaFold3. To further enhance the utility of AlphaFold3 predictions, we identify the pLDDT score of the TCR CDR3 region as an informative indicator of both structural correctness and functional relevance. Specifically, it enables up to 4.3% Top-1 success gain through reranking and captures mutation-induced affinity changes in over 80% of cases. Overall, our analysis would facilitate the practical usage of immune structure prediction models and guide the advancement of these models.