Structural consequences of beta-amino acid preorganization in a self-assembling alpha/beta-peptide: fundamental studies of foldameric helix bundles.
J Am Chem Soc
; 132(35): 12378-87, 2010 Sep 08.
Article
en En
| MEDLINE
| ID: mdl-20718422
ABSTRACT
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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1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Péptidos
/
Aminoácidos
Idioma:
En
Revista:
J Am Chem Soc
Año:
2010
Tipo del documento:
Article
País de afiliación:
Estados Unidos