HLA3DB: comprehensive annotation of peptide/HLA complexes enables blind structure prediction of T cell epitopes

The class I proteins of the major histocompatibility complex (MHC-I) display epitopic peptides derived from endogenous proteins on the cell surface for immune surveillance. Accurate modeling of peptide/HLA (pHLA, the human MHC) structures has been mired by conformational diversity of the central peptide residues, which are critical for recognition by T cell receptors. Here, analysis of X-ray crystal structures within a curated database (HLA3DB) shows that pHLA complexes encompassing multiple HLA allotypes present a discrete set of peptide backbone conformations. Leveraging these representative backbones, we employ a regression model trained on terms of a physically relevant energy function to develop a comparative modeling approach for nonamer peptide/HLA structures named RepPred. Our method outperforms the top pHLA modeling approach by up to 19% in terms of structural accuracy, and consistently predicts blind targets not included in our training set. Insights from our work provide a framework for linking conformational diversity with antigen immunogenicity and receptor cross-reactivity.