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Beta-peptide bundles with fluorous cores.

ABSTRACT: We reported recently that certain beta-peptides self-assemble spontaneously into cooperatively folded bundles whose kinetic and thermodynamic metrics mirror those of natural helix bundle proteins. The structures of four such beta-peptide bundles are known in atomic detail. These structures reveal a solvent-sequestered, hydrophobic core stabilized by a unique arrangement of leucine side chains and backbone methylene groups. Here we report that this hydrophobic core can be re-engineered to contain a fluorous subdomain while maintaining the characteristic beta-peptide bundle fold. Like alpha-helical bundles possessing fluorous cores, fluorous beta-peptide bundles are stabilized relative to hydrocarbon analogues and undergo cold denaturation. Beta-peptide bundles with fluorous cores represent the essential first step in the synthesis of orthogonal protein assemblies that can sequester selectively in an interstitial membrane environment.

SUBMITTER: Molski MA

PROVIDER: S-EPMC2842013 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Beta-peptide bundles with fluorous cores.

Molski Matthew A MA Goodman Jessica L JL Craig Cody J CJ Meng He H Kumar Krishna K Schepartz Alanna A

Journal of the American Chemical Society 20100301 11

We reported recently that certain beta-peptides self-assemble spontaneously into cooperatively folded bundles whose kinetic and thermodynamic metrics mirror those of natural helix bundle proteins. The structures of four such beta-peptide bundles are known in atomic detail. These structures reveal a solvent-sequestered, hydrophobic core stabilized by a unique arrangement of leucine side chains and backbone methylene groups. Here we report that this hydrophobic core can be re-engineered to contain ...[more]

PMID: 20196598

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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.

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Beta-peptide bundles with fluorous cores.

Publications

Beta-peptide bundles with fluorous cores.

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