Deciphering HLA-I motifs across HLA peptidomes improves neo-antigen predictions and identifies allostery regulating HLA specificity

PLoS Comput Biol. 2017 Aug 23;13(8):e1005725. doi: 10.1371/journal.pcbi.1005725. eCollection 2017 Aug.


The precise identification of Human Leukocyte Antigen class I (HLA-I) binding motifs plays a central role in our ability to understand and predict (neo-)antigen presentation in infectious diseases and cancer. Here, by exploiting co-occurrence of HLA-I alleles across ten newly generated as well as forty public HLA peptidomics datasets comprising more than 115,000 unique peptides, we show that we can rapidly and accurately identify many HLA-I binding motifs and map them to their corresponding alleles without any a priori knowledge of HLA-I binding specificity. Our approach recapitulates and refines known motifs for 43 of the most frequent alleles, uncovers new motifs for 9 alleles that up to now had less than five known ligands and provides a scalable framework to incorporate additional HLA peptidomics studies in the future. The refined motifs improve neo-antigen and cancer testis antigen predictions, indicating that unbiased HLA peptidomics data are ideal for in silico predictions of neo-antigens from tumor exome sequencing data. The new motifs further reveal distant modulation of the binding specificity at P2 for some HLA-I alleles by residues in the HLA-I binding site but outside of the B-pocket and we unravel the underlying mechanisms by protein structure analysis, mutagenesis and in vitro binding assays.

MeSH terms

  • Amino Acid Motifs / genetics*
  • Binding Sites / genetics
  • Histocompatibility Antigens Class I / chemistry*
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Peptides / analysis
  • Peptides / chemistry*
  • Peptides / genetics
  • Peptides / metabolism
  • Protein Binding / genetics
  • Proteome / chemistry*
  • Proteome / genetics
  • Proteome / metabolism
  • Proteomics / methods*


  • Histocompatibility Antigens Class I
  • Peptides
  • Proteome

Grant support

This work was supported by CADMOS funding through University of Lausanne to DG and MS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.