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PreprintCited by 2vaccines and immunoinformatics approachesProtein Structure and DynamicsChemical Synthesis and Analysis

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

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Gupta, Sagar, Nerli, Santrupti, Kandy, Sreeja Kutti, Mersky, Glenn L., Sgourakis, Nikolaos G.·2023·bioRxiv (Cold Spring Harbor Laboratory)
DOI 10.1101/2023.03.20.533510PMC PMC10055217

Preprint — published as 10.1038/s41467-023-42163-z · Paper page

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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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Metadata

Authors
Gupta, S., Nerli, S., Kandy, S. K., Mersky, G. L., & Sgourakis, N. G.
Affiliations
Children's Hospital of Philadelphia (US)
Corresponding author
Sgourakis, Nikolaos G.
ORCID
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2023-03-23
DOI
10.1101/2023.03.20.533510
PMC
PMC10055217
OpenAlex
W4360869991
Cited by
2
References
2
Citations by year
2024: 1 · 2023: 1
Type
posted content
Language
en
Open access
Locations
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Institute of General Medical Sciences (R35GM125034)
  • National Institute of Allergy and Infectious Diseases (R01AI143997)
  • National Institute of Diabetes and Digestive and Kidney Diseases (U01DK112217)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
Keywords
peptide-HLA complex, MHC class I, T cell epitopes, peptide backbone conformation, homology modeling, conformational heterogeneity, antigen immunogenicity, receptor cross-reactivity, HLA allotypes

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