title: Periodic variation in side-chain polarities of T-cell antigenic peptides correlates with their structure and activity.
abstract: We present an analysis that synthesizes information on the sequence, structure, and motifs of antigenic peptides, which previously appeared to be in conflict. Fourier analysis of T-cell antigenic peptides indicates a periodic variation in amino acid polarities of 3-3.6 residues per period, suggesting an amphipathic alpha-helical structure. However, the diffraction patterns of major histocompatibility complex (MHC) molecules indicate that their ligands are in an extended non-alpha-helical conformation. We present two mutually consistent structural explanations for the source of the alpha-helical periodicity, based on an observation that the side chains of MHC-bound peptides generally partition with hydrophobic (hydrophilic) side chains pointing into (out of) the cleft. First, an analysis of haplotype-dependent peptide motifs indicates that the locations of their defining residues tend to force a period 3-4 variation in hydrophobicity along the peptide sequence, in a manner consistent with the spacing of pockets in the MHC. Second, recent crystallographic determination of the structure of a peptide bound to a class II MHC molecule reveals an extended but regularly twisted peptide with a rotation angle of about 130 degrees. We show that similar structures with rotation angles of 100-130 degrees are energetically acceptable and also span the length of the MHC cleft. These results provide a sound physical chemical and structural basis for the existence of a haplotype-independent antigenic motif which can be particularly important in limiting the search time for antigenic peptides.
authors.affiliation: Department of Mathematics, Iowa State University, Ames 50011, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Cornette
authors.forename: H
authors.initials: H
authors.lastname: Margalit
authors.forename: J A
authors.initials: JA
authors.lastname: Berzofsky
authors.forename: C
authors.initials: C
authors.lastname: DeLisi
mesh_terms: D000941:Antigens / Q000737:chemistry* / Q000276:immunology; D018360:Crystallography, X-Ray; D005583:Fourier Analysis; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology*
chemical_list: D000941:Antigens; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II