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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.

SUBMITTER: Cornette JL

PROVIDER: S-EPMC41158 | biostudies-other | 1995 Aug

REPOSITORIES: biostudies-other

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Periodic variation in side-chain polarities of T-cell antigenic peptides correlates with their structure and activity.

Cornette J L JL Margalit H H Berzofsky J A JA DeLisi C C

Proceedings of the National Academy of Sciences of the United States of America 19950801 18

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 conform ...[more]

PMID: 7667297

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Project description:Helices are the most extensively studied secondary structures formed by ?-peptide foldamers. Among the five known ?-peptide helices, the 12-helix is particularly interesting because the internal hydrogen bond orientation and macrodipole are analogous to those of ?-peptide helices (?-helix and 3(10)-helix). The ?-peptide 12-helix is defined by i, i+3 C?O···H-N backbone hydrogen bonds and promoted by ?-residues with a five-membered ring constraint. The 12-helical scaffold has been used to generate ?-peptides with specific biological functions, for which diverse side chains must be properly placed along the backbone and, upon folding, properly arranged in space. Only two crystal structures of 12-helical ?-peptides have previously been reported, both for homooligomers of trans-2-aminocyclopentanecarboxylic acid (ACPC). Here we report five additional crystal structures of 12-helical ?-peptides, all containing residues that bear side chains. Four of the crystallized ?-peptides include trans-4,4-dimethyl-2-aminocyclopentanecarboxylic acid (dm-ACPC) residues, and the fifth contains a ?(3)-hPhe residue. These five ?-peptides adopt fully folded 12-helical conformations in the solid state. The new crystal structures, along with previously reported data, allow a detailed characterization of the 12-helical conformation; average backbone torsion angles of ?-residues and helical parameters are derived. These structural parameters are found to be similar to those for i, i+3 C?O···H-N hydrogen-bonded helices formed by other peptide backbones generated from ?- and/or ?-amino acids. The similarity between the conformational behavior of dm-ACPC and ACPC is consistent with previous NMR-based conclusions that 4,4-disubstituted ACPC derivatives are compatible with 12-helical folding. In addition, our data show how a ?(3)-residue is accommodated in the 12-helix, thus enhancing understanding of the diverse conformational behavior of this flexible class of ?-amino acids.

Dataset Information

Periodic variation in side-chain polarities of T-cell antigenic peptides correlates with their structure and activity.

Publications

Periodic variation in side-chain polarities of T-cell antigenic peptides correlates with their structure and activity.

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