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Impact of ?-Amino Acid Residue Preorganization on ?/?-Peptide Foldamer Helicity in Aqueous Solution.

ABSTRACT: ?/?-Peptide foldamers containing either ?(4)-amino acid residues or ring-constrained ?-amino acid residues have been reported to adopt 12-helical secondary structure in nonpolar solvents and in the solid state. These observations have engendered speculation that the seemingly flexible ?(4) residues have a high intrinsic helical propensity and that residue-based preorganization may not significantly stabilize the 12-helical conformation. However, the prior studies were conducted in environments that favor intramolecular H-bond formation. Here, we use 2D-NMR to compare the ability of ?(4) residues and cyclic ? residues to support 12-helix formation in more challenging environments, methanol and water. Both ? residue types support 12-helical folding in methanol, but only the cyclically constrained ? residues promote helicity in water. These results demonstrate the importance of residue-based preorganization strategies for achieving stable folding among short foldamers in aqueous solution.

SUBMITTER: Fisher BF

PROVIDER: S-EPMC5972013 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Impact of γ-Amino Acid Residue Preorganization on α/γ-Peptide Foldamer Helicity in Aqueous Solution.

Fisher Brian F BF Gellman Samuel H SH

Journal of the American Chemical Society 20160816 34

α/γ-Peptide foldamers containing either γ(4)-amino acid residues or ring-constrained γ-amino acid residues have been reported to adopt 12-helical secondary structure in nonpolar solvents and in the solid state. These observations have engendered speculation that the seemingly flexible γ(4) residues have a high intrinsic helical propensity and that residue-based preorganization may not significantly stabilize the 12-helical conformation. However, the prior studies were conducted in environments t ...[more]

PMID: 27529788

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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

Impact of ?-Amino Acid Residue Preorganization on ?/?-Peptide Foldamer Helicity in Aqueous Solution.

Publications

Impact of γ-Amino Acid Residue Preorganization on α/γ-Peptide Foldamer Helicity in Aqueous Solution.

Similar Datasets

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