Evaluation of Diverse α/β-Backbone Patterns for Functional α-Helix Mimicry: Analogues of the Bim BH3 Domain

• Published in: Journal of the American Chemical Society 2012-01, Vol.134 (1), p.315-323
• Main Authors: Boersma, Melissa D, Haase, Holly S, Peterson-Kaufman, Kimberly J, Lee, Erinna F, Clarke, Oliver B, Colman, Peter M, Smith, Brian J, Horne, W. Seth, Fairlie, W. Douglas, Gellman, Samuel H
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Apoptosis Regulatory Proteins - chemistry; Apoptosis Regulatory Proteins - metabolism; Bcl-2-Like Protein 11; bcl-X Protein - metabolism; Crystallography, X-Ray; Membrane Proteins - chemistry; Membrane Proteins - metabolism; Mice; Models, Molecular; Molecular Sequence Data; Myeloid Cell Leukemia Sequence 1 Protein; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Protein Structure, Secondary; Protein Structure, Tertiary; Proto-Oncogene Proteins - chemistry; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja207148m

Peptidic oligomers that contain both α- and β-amino acid residues, in regular patterns throughout the backbone, are emerging as structural mimics of α-helix-forming conventional peptides (composed exclusively of α-amino acid residues). Here we describe a comprehensive evaluation of diverse α/β-peptide homologues of the Bim BH3 domain in terms of their ability to bind to the BH3-recognition sites on two partner proteins, Bcl-xL and Mcl-1. These proteins are members of the anti-apoptotic Bcl-2 family, and both bind tightly to the Bim BH3 domain itself. All α/β-peptide homologues retain the side-chain sequence of the Bim BH3 domain, but each homologue contains periodic α-residue → β3-residue substitutions. Previous work has shown that the ααβαααβ pattern, which aligns the β3-residues in a ’stripe’ along one side of the helix, can support functional α-helix mimicry, and the results reported here strengthen this conclusion. The present study provides the first evaluation of functional mimicry by ααβ and αααβ patterns, which cause the β3-residues to spiral around the helix periphery. We find that the αααβ pattern can support effective mimicry of the Bim BH3 domain, as manifested by the crystal structure of an α/β-peptide bound to Bcl-xL, affinity for a variety of Bcl-2 family proteins, and induction of apoptotic signaling in mouse embryonic fibroblast extracts. The best αααβ homologue shows substantial protection from proteolytic degradation relative to the Bim BH3 α-peptide.