Amphiphilic Peptide–Polymer Conjugates with Side-Conjugation a Nikhil Dube, Andrew D. Presley, Jessica Y. Shu, Ting Xu* Introduction As an emerging family of soft matter, hybrid materials based on peptide/proteins and polymers have the potential to achieve structural control over multiple length scales, down to the molecular level, and exhibit enriched chemical heterogeneity and functionalities inherent to peptides/ proteins. [1–15] The chemical nature of conjugated polymers and the architecture of the protein–polymer conjugate have profound effects on the protein structure and functional- ities and the self-assembly of peptide–polymer conju- gates. [16–28] Hydrophilic peptide–polymer conjugates with different architectures have been prepared and studied. [18–23] Conjugating poly(ethylene glycol) (PEG) to the exterior of the helix bundle enhances peptide helicity, Feature Article N. Dube, A. D. Presley, J. Y. Shu, T. Xu Department of Materials Science and Engineering, University of California, Berkeley, California 94720, USA E-mail: tingxu@berkeley.edu T. Xu Department of Chemistry, University of California, Berkeley, California 94720, USA T. Xu Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA a : Supporting information for this article is available from the Wiley Online Library or from the author. Polymers conjugated to the exterior of a protein mediate its interactions with surroundings, enhance its processability and can be used to direct its macroscopic assemblies. Most studies to date have focused on peptide–polymer conjugates based on hydrophilic polymers. Engineering amphiphilicity into protein motifs by covalently linking hydrophobic polymers has the potential to interface peptides and proteins with synthetic polymers, organic solvents, and lipids to fabricate functional hybrid materials. Here, we synthesized amphiphilic peptide–polymer con- jugates in which a hydrophobic polymer is conjugated to the exterior of a heme-binding four- helix bundle and systematically investigated the effects of the hydrophobicity of the conjugated polymer on the peptide structure and the integrity of the heme-binding pocket. In aqueous solution with surfactants present, the side-conjugated hydrophobic polymers unfold peptides and may induce an a-helix to b-sheet conformational transition. These effects decrease as the polymer becomes less hydrophobic and directly correlate with the polymer hydrophobicity. Upon adding organic solvent to solubilize the hydro- phobic polymers, however, the deleterious effects of hydrophobic polymers on the peptide structures can be eliminated. Present studies demonstrate that protein structure is sensitive to the local environment. It is feasible to dis- solve amphiphilic peptide–polymer conjugates in organic solvents to enhance their solution processability while maintaining the protein structures. 344 Macromol. Rapid Commun. 2011, 32, 344–353 ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim wileyonlinelibrary.com DOI: 10.1002/marc.201000603