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Differential impact of ? and ? residue preorganization on ?/?/?-peptide helix stability in water.

ABSTRACT: Cyclic constraints have proven to be very effective for preorganizing ?-amino acid residues and thereby stabilizing ?- and ?/?-peptide helices, but little is known about possible preorganization effects among ? residues. Here we assess and compare the impact of cyclic preorganization of ? and ? residues in the context of a specific ?/?/?-peptide helix. The results show that ? residue preorganization is critical for helix stability but that ? residue preorganization is less important.

SUBMITTER: Shin YH

PROVIDER: S-EPMC3815483 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Differential impact of β and γ residue preorganization on α/β/γ-peptide helix stability in water.

Shin Young-Hee YH Mortenson David E DE Satyshur Kenneth A KA Forest Katrina T KT Gellman Samuel H SH

Journal of the American Chemical Society 20130523 22

Cyclic constraints have proven to be very effective for preorganizing β-amino acid residues and thereby stabilizing β- and α/β-peptide helices, but little is known about possible preorganization effects among γ residues. Here we assess and compare the impact of cyclic preorganization of β and γ residues in the context of a specific α/β/γ-peptide helix. The results show that β residue preorganization is critical for helix stability but that γ residue preorganization is less important. ...[more]

PMID: 23701135

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Project description:We report high-resolution crystal structures of six new alpha/beta-peptide foldamers that have a regular alpha-residue/alpha-residue/beta-residue (alphaalphabeta) backbone repeat pattern. All of these foldamers were crystallized from aqueous solution, and all display four-helix bundle quaternary structure in the crystalline state. These oligomers are based on the well-studied 33-residue alpha-peptide GCN4-pLI, which is an engineered derivative of the dimerization domain of GCN4, a yeast transcription factor. GCN4-pLI forms a stable tetramer in solution and crystallizes as a four-helix bundle (Harbury et al. Science 1993, 262, 1401-1407). Previously we described a foldamer (designated 1 here) that was generated from GCN4-pLI by replacing every third alpha-amino acid residue with the homologous beta(3)-amino acid residue; this alphaalphabeta oligomer retains the side chain sequence of the original alpha-peptide, but the backbone contains 11 additional CH(2) units, which are evenly distributed (Horne et al. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 9151-9156). Despite the expanded backbone, 1 was found to retain the ability to form a tetrameric quaternary structure in which the individual molecules adopt an alpha-helix-like conformation. Here we compare nine analogues of 1 that have the same alphaalphabeta backbone but in which one or more of the flexible beta(3)-amino acid residues is/are replaced with an analogous cyclic beta-residue. The motivation for beta(3)-->cyclic replacements is to enhance conformational stability; however, a crystal structure of the one previously reported example (designated 2 here) revealed a "stammer" distortion of the helix-bundle architecture relative to 1. The results reported here suggest that the stammer is a peculiarity of 2, because all six of the new alpha/beta-peptides display undistorted four-helix bundle quaternary structures. More broadly, our results indicate that beta(3)-->cyclic replacements are generally well-accommodated in helix-bundle quaternary structure, but that such replacements can be destabilizing in certain instances.

Dataset Information

Differential impact of ? and ? residue preorganization on ?/?/?-peptide helix stability in water.

Publications

Differential impact of β and γ residue preorganization on α/β/γ-peptide helix stability in water.

Similar Datasets

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