SwiftMHC: A High-Speed Attention Network for MHC-Bound Peptide Identification and 3D Modeling

Identifying tumor peptides that bind patient MHC proteins and elicit immune responses is central to immunotherapy, yet progress remains limited to a handful of well-studied alleles. Structure-based methods generalize better than sequence-only models but are constrained by the high computational cost of 3D modeling. We present SwiftMHC, the fastest structure-based framework for peptide–MHC (pMHC) modeling and binding affinity prediction. SwiftMHC predicts peptide–MHC binding in 0.009 sec/case in batch mode on a single A100 GPU—nearly an order of magnitude faster than leading sequence-based methods such as NetMHCpan 4.1 (0.081 sec/case)—while performing competitively in predictive accuracy. In addition to affinity estimation, SwiftMHC generates all-atom 3D pMHC structures and achieves a median Cα-RMSD of 1.32 Å against X-ray benchmarks, matching or better than the accuracy of state-of-the-art approaches (e.g., AlphaFold with fine-tuning) but running thousands of times faster (excluding disk-writing time). These results demonstrate the power of task-specific AI trained on physics-derived synthetic data to overcome the scarcity of experimental structures. Optimized for HLA-A*02:01 9-mers but readily extensible to other alleles, SwiftMHC enables rapid and accurate identification of peptides distinct from self at T-cell–exposed surfaces. This capability may expand immunotherapy targets, improve the safety of TCR-based therapies, and accelerate the development of next-generation cancer immunotherapies.