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bioRxiv · 10.1101/2023.03.20.533510

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

Gupta, S.·Nerli, S.·Kandy, S. K.·Mersky, G. L.·Sgourakis, N. G.
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Abstract

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.

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Gupta, S., Nerli, S., Kandy, S. K., Mersky, G. L., Sgourakis, N. G.. 2023-03-23. HLA3DB: comprehensive annotation of peptide/HLA complexes enables blind structure prediction of T cell epitopes. https://doi.org/10.1101/2023.03.20.533510

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