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Rosetta FlexPepDock to predict peptide-MHC binding: An approach for non-canonical amino acids

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  • Nathaniel Bloodworth
  • Natália Ruggeri Barbaro
  • Rocco Moretti
  • David G Harrison
  • Jens Meiler

Abstract

Computation methods that predict the binding of peptides to MHC-I are important tools for screening and identifying immunogenic antigens and have the potential to accelerate vaccine and drug development. However, most available tools are sequence-based and optimized only for peptides containing the twenty canonical amino acids. This omits a large number of peptides containing non-canonical amino acids (NCAA), or residues that undergo varied post-translational modifications such as glycosylation or phosphorylation. These modifications fundamentally alter peptide immunogenicity. Similarly, existing structure-based methods are biased towards canonical peptide backbone structures, which may or may not be preserved when NCAAs are present. Rosetta FlexPepDock ab-initio is a structure-based computational protocol able to evaluate peptide-receptor interaction where no prior information of the peptide backbone is known. We benchmarked FlexPepDock ab-initio for docking canonical peptides to MHC-I, and illustrate for the first time the method’s ability to accurately model MHC-I bound epitopes containing NCAAs. FlexPepDock ab-initio protocol was able to recapitulate near-native structures (≤1.5Å) in the top lowest-energy models for 20 out of 25 cases in our initial benchmark. Using known experimental binding affinities of twenty peptides derived from an influenza-derived peptide, we showed that FlexPepDock protocol is able to predict relative binding affinity as Rosetta energies correlate well with experimental values (r = 0.59, p = 0.006). ROC analysis revealed 80% true positive and a 40% false positive rate, with a prediction power of 93%. Finally, we demonstrate the protocol’s ability to accurately recapitulate HLA-A*02:01 bound phosphopeptide backbone structures and relative binding affinity changes, the theoretical structure of the lymphocytic choriomeningitis derived glycosylated peptide GP392 bound to MHC-I H-2Db, and isolevuglandin-adducted peptides. The ability to use non-canonical amino acids in the Rosetta FlexPepDock protocol may provide useful insight into critical amino acid positions where the post-translational modification modulates immunologic responses.

Suggested Citation

  • Nathaniel Bloodworth & Natália Ruggeri Barbaro & Rocco Moretti & David G Harrison & Jens Meiler, 2022. "Rosetta FlexPepDock to predict peptide-MHC binding: An approach for non-canonical amino acids," PLOS ONE, Public Library of Science, vol. 17(12), pages 1-16, December.
  • Handle: RePEc:plo:pone00:0275759
    DOI: 10.1371/journal.pone.0275759
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