Nanostructured Materials DOI: 10.1002/anie.200704372 Nanofibers and Lyotropic Liquid Crystals from a Class of Self-Assembling b-Peptides** William C. Pomerantz, ViranyM. Yuwono, Claire L. Pizzey, Jeffery D. Hartgerink,* Nicholas L. Abbott,* and Samuel H. Gellman* Lyotropic liquid-crystalline (LC) phases, in other words, LC phases induced by the presence of a solvent, form through the assembly of large anisometric particles, such as rigid poly- mers, [1] viruses, [2] or inorganic rods, [3] as a result of excluded volume interactions (Onsager theory). [4] Small molecules can form lyotropic LC phases if they undergo self-assembly to generate anisometric nanostructures. Aqueous LC phases are commonly observed for small molecules that have clearly segregated hydrophilic and lipophilic segments, such as detergents and lipids. [1a] For such “globally amphiphilic” molecules it is believed that hydrophobically induced associ- ation of the lipophilic segments drives the assembly that underlies LC formation. Chromonic LCs are formed from a distinct class of small molecules that self-assemble in water but do not display a simple segregation of hydrophilic and lipophilic segments [5] (they are non-globally amphiphilic). It is difficult to understand how the self-assembly of chromonic molecules (i.e., molecules that form chromonic LCs) is related to the nature and internal organization of lipophilic surfaces because these molecular properties cannot readily be altered in an incremental fashion. Here we describe a class of oligomers that, like the chromonic molecules, are not globally amphiphilic but nevertheless form LC phases in water. The intrinsic modularity of these oligomers allows rational and systematic modification of lipophilic or hydrophilic compo- nents, which enables us to define key features that are required for LC formation. Short oligomers of b-amino acids (b-peptides) are attrac- tive for systematic study of assembly processes leading to LCs because b-peptides can display a diverse range of function- alized side chains, and these oligomers fold into compact and stable conformations that orient the side chains in predictable ways. [6] The most widely studied b-peptide secondary struc- ture is the 14-helix, which is defined by i, i2C =O···HN hydrogen bonds (14-membered ring) between backbone amides and contains approximately three residues per helical turn. The high stability of the 14-helix, in combination with ready manipulation of b-peptide sequence, permits consid- erable control over the nanopatterning of chemical function- ality in three dimensions. Here we exploit these features by designing b-peptide oligomers that fold into helical nano- structures and are decorated with functional groups in patterns that either do or do not confer global amphiphilicity on the 14-helix. As described below, this sequence-based patterning strategy has led to the discovery of b-peptide oligomers that are non-globally amphiphilic and exhibit liquid crystallinity in aqueous solution. Our initial experiments focused on sequence isomers A and iso-A (Figure 1). The latter has a repeating triad motif containing trans-2-aminocyclohexanecarboxylic acid (ACHC), b 3 homophenylalanine (b 3 hPhe), and b 3 hLys resi- dues; the lipophilic–lipophilic–hydrophilic ACHC-b 3 hPhe- b 3 hLys sequence repeat pattern in iso-A leads to a globally amphiphilic nanostructure. In contrast, the sequence of A does not lead to global segregation of lipophilic and hydro- philic side chains in the 14-helix, but rather to a distribution of lipophilic and hydrophilic side chains around the entire periphery of the helix (Figure 1). The helix from A is defined as non-globally amphiphilic. Since global amphiphilicity of b- peptides has previously been associated with liquid crystal- linity, [7] we expected iso-A but not A to form a LC phase in water. Surprisingly, however, strong birefringence was observed for aqueous solutions containing A  6.5wt%, (36 mm, Figure 2), but no birefringence was detected for solutions of iso-A up to the solubility limit > 10wt%(57mm, Figure 2). Inspection of the birefringent domains at high magnifica- tion shows an absence of optical textures characteristic of higher ordered mesophases such as smectics and cholester- ics; [8] these observations lead us to conclude that the mesophase is likely nematic. The unexpected ability of the non-globally amphiphilic helix to form an LC phase is [*] V. M. Yuwono, Prof. J. D. Hartgerink Department of Chemistry and Bioengineering Rice University 6100 Main Street MS60, Houston, TX 77005 (USA) Fax: (+ 1) 713-348-4201 E-mail: jdh@rice.edu W. C. Pomerantz, Prof. S. H. Gellman Department of Chemistry University of Wisconsin-Madison 1101 University Avenue, Madison, WI 53706 (USA) Fax: (+ 1) 608-265-4534 E-mail: gellman@chem.wisc.edu C. L. Pizzey, Prof. N. L. Abbott Department of Chemical and Biological Engineering University of Wisconsin-Madison 1415 Engineering Drive, Madison, WI 53706 (USA) Fax: (+ 1) 608-262-5434 E-mail: abbott@engr.wisc.edu [**] This research was supported by University of Wisconsin-Madison Nanoscale Science and Engineering Center (NSF grant DMR- 0425880). V.M.Y. was supported by the Welch Foundation research grant C-1557. Authors kindly thank PepTech for a generous supply of several b-amino acids at a discounted price and Arun Yethiraj for helpful conversations during the preparation of this manuscript. Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author. Angewandte Chemie 1241 Angew. Chem. Int. Ed. 2008, 47, 1241 –1244 # 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim