Fast and accurate modeling of TCR-peptide-MHC complexes using tFold-TCR

Alpha-beta T cell receptor ( αβ TCR) recognition of peptide-major histocompatibility complexes (pMHCs) is a cornerstone of the adaptive immune system. Fast and accurate modeling of TCR-pMHC structures is crucial for understanding TCR recognition of pMHCs at the molecular level, which is essential for the development of TCR-based therapeutics and vaccines. Despite significant interest, this challenge remains unresolved due to the diversity of TCR-pMHC interactions and limited structural data. Here, we present tFold-TCR, a high-throughput, end-to-end universal model for predicting three-dimensional (3D) atomic-level structures of TCR-pMHC complexes, capable of predicting TCRs of different classes and MHC structures from diverse systems. tFold-TCR leverages a specially trained, protein-protein interaction-sensitive large protein language model to extract intra and inter-chain residue contact information and evolutionary relationships, bypassing the need for multiple sequence alignment (MSA) searches. It also features innovative structure prediction and flexible docking modules to enhance accuracy, particularly for interacting contacts. Compared to existing methods, including AlphaFold-3, tFold-TCR demonstrates a 30.7% increase in prediction success rate evaluated by DockQ and is over 25 times faster. These advancements enable large-scale structural characterization of TCRs and their interactions with pMHCs. Utilizing this capability, we constructed TCRStructDB, the largest database of TCR-pMHC structures to date, encompassing 2.2 million TCRs, 0.8 million pMHCs, and 45,000 TCR-pMHC complexes. TCRStructDB provides unprecedented insights into one of the most diverse receptor-ligand interactions in biology.