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Issue 1, 2013
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Remodeling a β-peptide bundle

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Natural biopolymers fold with fidelity, burying diverse side chains into well-packed cores and protecting their backbones from solvent. Certain β-peptide oligomers assemble into bundles of defined octameric stoichiometry that resemble natural proteins in many respects. These β-peptide bundles are thermostable, fold cooperatively, exchange interior amide N–H protons slowly, exclude hydrophobic dyes, and can be characterized at high resolution using X-ray crystallography – just like many proteins found in nature. But unlike natural proteins, all octameric β-peptide bundles contain a sequence-uniform hydrophobic core composed of 32 leucine side chains. Here we apply rational design principles, including the Rosetta computational design methodology, to introduce sequence diversity into the bundle core while retaining the characteristic β-peptide bundle fold. Using circular dichroism spectroscopy and analytical ultracentrifugation, we confirmed the prediction that an octameric bundle still assembles upon a major remodelling of its core: the mutation of sixteen core β-homo-leucine side chains into sixteen β-homo-phenylalanine side chains. Nevertheless, the bundle containing a partially β-homo-phenylalanine core poorly protects interior amide protons from exchange, suggesting molten-globule-like properties. We further improve stability by the incorporation of eight β-homo-pentafluorophenyalanine side chains, giving an assembly with amide protection factors comparable to prior well-structured bundles. By demonstrating that their cores tolerate significant sequence variation, the β-peptide bundles reported here represent a starting point for the “bottom-up” construction of β-peptide assemblies possessing both structure and sophisticated function.

Graphical abstract: Remodeling a β-peptide bundle

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Publication details

The article was received on 07 Apr 2012, accepted on 10 Sep 2012 and first published on 21 Sep 2012

Article type: Edge Article
DOI: 10.1039/C2SC21117C
Citation: Chem. Sci., 2013,4, 319-324

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    Remodeling a β-peptide bundle

    M. A. Molski, J. L. Goodman, F. Chou, D. Baker, R. Das and A. Schepartz, Chem. Sci., 2013, 4, 319
    DOI: 10.1039/C2SC21117C

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