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Cited by 26vaccines 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, Kutti Kandy, Sreeja, Mersky, Glenn L., Sgourakis, Nikolaos G.·2023·Nature Communications
DOI 10.1038/s41467-023-42163-zPMC PMC10564892

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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 peptides bound to the human MHC, HLA, 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 our curated database (HLA3DB) shows that pHLA complexes encompassing multiple HLA allotypes present a discrete set of peptide backbone conformations. Leveraging these backbones, we employ a regression model trained on terms of a physically relevant energy function to develop a comparative modeling approach for nonamer pHLA structures named RepPred. Our method outperforms the top pHLA modeling approach by up to 19% in structural accuracy, and consistently predicts blind targets not included in our training set. Insights from our work may be applied towards predicting antigen immunogenicity, and receptor cross-reactivity.

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Fig. 1 Analysis of pHLA structures in HLA3DB uncovers the basis for peptide conformational diversity. a Distribution of pHLA structures in HLA3DB by supertype for HLA-A and HLA-B and single-resolution allotype for HLA-C, HLA-E, and HLA-G. b Schematic depicting how anchor class and anchor distance are defined using the ∆7 anchor class as an example. Cα atoms of anchor residues are shown as green spheres and connected by an orange solid line depicting the anchor distance. B and F pockets are shaded in pink and blue, respectively, and the remainder of the HLA is colored in gray. c Distribution of anchor distances for each anchor class with the center indicating the median (∆6 pHLA structures: n = 15; ∆7 pHLA structures: n = 303; ∆8 pHLA structures: n = 75). Whiskers extend to the furthest values that lie within the 75th and 25th percentile value ± 1.5 times the interquartile range. Outliers are shown in black and pink circles with pink data points elaborated in Supplementary Fig. 1c–f. Peptide backbones corresponding to the median anchor distance of each anchor class are shown above each respective boxplot (∆6: PDB ID 1E28 [10.2210/pdb1E28/pdb], ∆7: PDB ID 1K5N [10.2210/pdb1K5N/pdb], ∆8: PDB ID 3I6K [10.2210/pdb3I6K/pdb]). d A schematic of the fixed-local framework for conformational diversity. On the right, the inset highlights the central bulge of the peptide and the respective dihedral angles in orange dashed sectors. Backbone heavy atoms are shown as spheres. e General Ramachandran plot showing dihedral angle pairs satisfying the anchor distance distribution seen in the ∆7 anchor class. Favorable overlaps are colored green, allowed overlaps are colored cream, and disallowed overlaps are colored red. Favorable regions are shaded blue, allowed regions are shaded light blue, and unfavorable regions are shaded white. PPII conformation is shown as a red diamond at (−75°, +145°). f Backbone of a de novo designed polyglycine nonamer with all dihedral angles set to the PPII angle (−75°, +145°). Cα atoms of anchor positions are shown as spheres and connected via an orange dotted line to indicate anchor distance. g General Ramachandran plots of all ∆7 peptides (n = 303). Plots are shaded identically to (b) with discrete points instead of shaded surfaces.
Fig. 1 Analysis of pHLA structures in HLA3DB uncovers the basis for peptide conformational diversity. a Distribution of pHLA structures in HLA3DB by supertype for HLA-A and HLA-B and single-resolution allotype for HLA-C, HLA-E, and HLA-G. b Schematic depicting how anchor class and anchor distance are defined using the ∆7 anchor class as an example. Cα atoms of anchor residues are shown as green spheres and connected by an orange solid line depicting the anchor distance. B and F pockets are shaded in pink and blue, respectively, and the remainder of the HLA is colored in gray. c Distribution of anchor distances for each anchor class with the center indicating the median (∆6 pHLA structures: n = 15; ∆7 pHLA structures: n = 303; ∆8 pHLA structures: n = 75). Whiskers extend to the furthest values that lie within the 75th and 25th percentile value ± 1.5 times the interquartile range. Outliers are shown in black and pink circles with pink data points elaborated in Supplementary Fig. 1c–f. Peptide backbones corresponding to the median anchor distance of each anchor class are shown above each respective boxplot (∆6: PDB ID 1E28 [10.2210/pdb1E28/pdb], ∆7: PDB ID 1K5N [10.2210/pdb1K5N/pdb], ∆8: PDB ID 3I6K [10.2210/pdb3I6K/pdb]). d A schematic of the fixed-local framework for conformational diversity. On the right, the inset highlights the central bulge of the peptide and the respective dihedral angles in orange dashed sectors. Backbone heavy atoms are shown as spheres. e General Ramachandran plot showing dihedral angle pairs satisfying the anchor distance distribution seen in the ∆7 anchor class. Favorable overlaps are colored green, allowed overlaps are colored cream, and disallowed overlaps are colored red. Favorable regions are shaded blue, allowed regions are shaded light blue, and unfavorable regions are shaded white. PPII conformation is shown as a red diamond at (−75°, +145°). f Backbone of a de novo designed polyglycine nonamer with all dihedral angles set to the PPII angle (−75°, +145°). Cα atoms of anchor positions are shown as spheres and connected via an orange dotted line to indicate anchor distance. g General Ramachandran plots of all ∆7 peptides (n = 303). Plots are shaded identically to (b) with discrete points instead of shaded surfaces.CC BY · PubMed Central
Fig. 2 Unbiased classification reveals conserved peptide backbones across HLA allotypes. a A schematic of the greedy algorithm used to select discrete peptide backbones. b A two-dimensional PCA plot standardized with the sine of the dihedral angles of P4 to P7 explaining 66% of the variance. c Historical analysis of the cumulative number of ∆7 structures (blue) and discrete peptide backbones (red) in HLA3DB as determined iteratively by the greedy algorithm. d The proportion of supertype in each discrete peptide’s set of neighbors. The number of neighbors for each discrete peptide is shown in the right y-axis.
Fig. 2 Unbiased classification reveals conserved peptide backbones across HLA allotypes. a A schematic of the greedy algorithm used to select discrete peptide backbones. b A two-dimensional PCA plot standardized with the sine of the dihedral angles of P4 to P7 explaining 66% of the variance. c Historical analysis of the cumulative number of ∆7 structures (blue) and discrete peptide backbones (red) in HLA3DB as determined iteratively by the greedy algorithm. d The proportion of supertype in each discrete peptide’s set of neighbors. The number of neighbors for each discrete peptide is shown in the right y-axis.CC BY · PubMed Central
Fig. 3 Exhaustive enumeration of peptide sequence space reveals biases imposed by different backbone conformations. a A schematic of the exhaustive structural modeling conducted to augment the existing peptide sequence space for HLA-A*02:01. b Kullback–Leibler (KL) divergence between each of the predicted sequence space of the five most common HLA-A*02:01 backbones represented by PDB IDs and HLA-A*02:01 reference sequence space. A comparison between the eluted peptides bound to HLA-A*68:01 and those bound to HLA-A*02:01 was included as a negative control. c Peptide sequence logos of all eluted peptides shown to bind to HLA-A*02:01 via the IEDB (n = 32,483) and from structural modeling results (n = 7840). Created using Seq2Logo90. d Structural overlay of the peptide backbones (5HHQ [10.2210/pdb5HHQ/pdb], blue and 6VR1 [10.2210/pdb6VR1/pdb], orange) bound to HLA-A*02:01 (gray) with the peptide Cα atoms shown as spheres. e An enlarged view of the middle of the peptide with side chains depicted for P3 and P5. Coloring of the peptide backbone and side chain is identical to (d). Steric hindrance is shown as a red curve. f Structural model of the 6VR1 [10.2210/pdb6VR1/pdb] peptide backbone with P5 mutated to aspartate, as shown in green. A hydrogen bond is shown as a dashed black line.
Fig. 3 Exhaustive enumeration of peptide sequence space reveals biases imposed by different backbone conformations. a A schematic of the exhaustive structural modeling conducted to augment the existing peptide sequence space for HLA-A*02:01. b Kullback–Leibler (KL) divergence between each of the predicted sequence space of the five most common HLA-A*02:01 backbones represented by PDB IDs and HLA-A*02:01 reference sequence space. A comparison between the eluted peptides bound to HLA-A*68:01 and those bound to HLA-A*02:01 was included as a negative control. c Peptide sequence logos of all eluted peptides shown to bind to HLA-A*02:01 via the IEDB (n = 32,483) and from structural modeling results (n = 7840). Created using Seq2Logo90. d Structural overlay of the peptide backbones (5HHQ [10.2210/pdb5HHQ/pdb], blue and 6VR1 [10.2210/pdb6VR1/pdb], orange) bound to HLA-A*02:01 (gray) with the peptide Cα atoms shown as spheres. e An enlarged view of the middle of the peptide with side chains depicted for P3 and P5. Coloring of the peptide backbone and side chain is identical to (d). Steric hindrance is shown as a red curve. f Structural model of the 6VR1 [10.2210/pdb6VR1/pdb] peptide backbone with P5 mutated to aspartate, as shown in green. A hydrogen bond is shown as a dashed black line.CC BY · PubMed Central
Fig. 4 Structural modeling of ∆7 nonamer/HLA complexes (RepPred) and comparison to state-of-the-art methods. a Full workflow of the RepPred structural modeling method. b Boxplots showing the distribution of the D-score and peptide backbone heavy atom RMSD of RepPred and six state-of-the-art methods, sorted by publication date, for A02 targets with the center indicating the median (Best model, RepPred, ref2015: n = 102; GradDock: n = 90; APE-Gen: n = 99; Keller: n = 101; PANDORA: n = 100; AlphaFold: n = 101; AF-FineTune: n = 93). Whiskers extend to the furthest values that lie within the 75th and 25th percentile value ± 1.5 times the interquartile range and outliers are shown in black circles. An orange dashed line is at a D-score of 1.5 and an RMSD of 1.0. c Structural superposition of the RepPred model (template PDB ID 1OF2 [10.2210/pdb1OF2/pdb]) and native structure (PDB ID 7U21 [10.2210/pdb7U21/pdb]) of the blind target melanoma antigen AVGSYVYSV bound to HLA-A*02:01. The target sequence and allotype is written below the structure followed by the sequence and allotype of the template. d Comparison of RepPred against AF-FT for A02 and non-A02 targets. Accuracy is shown as a percentage over each bar. e Structural superposition of the RepPred model (template PDB ID 6MT6 [10.2210/pdb6MT6/pdb]) and native structure (PDB ID 7R7Y [10.2210/pdb7R7Y/pdb]) of the blind target HIV antigen QATQEVKNW bound to HLA-B*57:01. Formatting is identical to (c).
Fig. 4 Structural modeling of ∆7 nonamer/HLA complexes (RepPred) and comparison to state-of-the-art methods. a Full workflow of the RepPred structural modeling method. b Boxplots showing the distribution of the D-score and peptide backbone heavy atom RMSD of RepPred and six state-of-the-art methods, sorted by publication date, for A02 targets with the center indicating the median (Best model, RepPred, ref2015: n = 102; GradDock: n = 90; APE-Gen: n = 99; Keller: n = 101; PANDORA: n = 100; AlphaFold: n = 101; AF-FineTune: n = 93). Whiskers extend to the furthest values that lie within the 75th and 25th percentile value ± 1.5 times the interquartile range and outliers are shown in black circles. An orange dashed line is at a D-score of 1.5 and an RMSD of 1.0. c Structural superposition of the RepPred model (template PDB ID 1OF2 [10.2210/pdb1OF2/pdb]) and native structure (PDB ID 7U21 [10.2210/pdb7U21/pdb]) of the blind target melanoma antigen AVGSYVYSV bound to HLA-A*02:01. The target sequence and allotype is written below the structure followed by the sequence and allotype of the template. d Comparison of RepPred against AF-FT for A02 and non-A02 targets. Accuracy is shown as a percentage over each bar. e Structural superposition of the RepPred model (template PDB ID 6MT6 [10.2210/pdb6MT6/pdb]) and native structure (PDB ID 7R7Y [10.2210/pdb7R7Y/pdb]) of the blind target HIV antigen QATQEVKNW bound to HLA-B*57:01. Formatting is identical to (c).CC BY · PubMed Central

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Metadata

Authors
Gupta, S., Nerli, S., Kutti Kandy, S., Mersky, G. L., & Sgourakis, N. G.
Affiliations
Children's Hospital of Philadelphia (US)
Corresponding author
Sgourakis, Nikolaos G.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-10-10
Volume
14
Issue
1
Pages
6349-6349
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-42163-z
PMC
PMC10564892
OpenAlex
W4387491415
Cited by
26
References
5
Citations by year
2026: 5 · 2025: 6 · 2024: 10 · 2023: 5
FWCI
2.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (5R35GM125034)
  • Division of Intramural Research, National Institute of Allergy and Infectious Diseases (5R01AI143997)
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, T cell epitopes, MHC class I, homology modeling, peptide backbone conformation, HLA allotypes, X-ray crystal structure, antigen immunogenicity, receptor cross-reactivity
MeSH terms
Histocompatibility Antigens, Humans, Peptides, Receptors, Antigen, T-Cell, Histocompatibility Antigens Class I, Epitopes, T-Lymphocyte

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