Controlling the Conformation of Oligocholate Foldamers by Surfactant Micelles Zhenqi Zhong and Yan Zhao* Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011-3111
[email protected] ReceiVed April 1, 2008
Fluorescence resonance energy transfer (FRET) occurred readily in a cholate hexamer labeled with a naphthyl donor and a dansyl acceptor at the chain ends when the hexamer was solubilized by sodium dodecyl sulfate (SDS) micelles in water. Independence of the energy transfer efficiency over 1-70 mM SDS suggested that the energy transfer resulted from the folding of the hexamer instead of its intermolecular aggregation within the micelle. Upon addition of sodium chloride to the solution, energy transfer became less efficient, indicating unfolding of the oligocholate. In contrast, the oligocholate stayed folded in the micelle of nonionic Brij 30, in the presence or absence of NaCl. These results suggested that the oligocholate preferred to fold within the small spherical SDS micelles but unfold when the preference for spherical over rodlike micelles was not strong enough to overcome the tendency for the oligocholate to unfold.
Introduction Foldamers have attracted a great deal of interest in recent years as the synthetic analogues of biomolecules that adopt compact, ordered conformations.1–3 On the fundamental level, learning to control the conformation of a chain-like molecule allows chemists to gain insight into the folding of biological polymers. Also, the conformation of a molecule dictates its size, shape, and the distribution of functional groups, all of which directly affect its chemical and physical properties. Therefore, on the practical level, conformational control can help chemists * To whom correspondence should be addressed. Phone: 515-294-5845. Fax: 515-294-0105. (1) For several representative reviews, see: (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173–180. (b) Kirshenbaum, K.; Zuckermann, R. N.; Dill, K. A. Curr. Opin. Struct. Biol. 1999, 9, 530–535. (c) Stigers, K. D.; Soth, M. J.; Nowick, J. S. Curr. Opin. Chem. Biol. 1999, 3, 714–723. (d) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S. Chem. ReV. 2001, 101, 3893– 4012. (e) Cubberley, M. S.; Iverson, B. L. Curr. Opin. Chem. Biol. 2001, 5, 650–653. (f) Sanford, A. R.; Gong, B. Curr. Org. Chem. 2003, 7, 1649–1659. (g) Martinek, T. A.; Fulop, F. Eur. J. Biochem. 2003, 270, 3657–3666. (h) Cheng, R. P. Curr. Opin. Struct. Biol. 2004, 14, 512–520. (i) Huc, I. Eur. J. Org. Chem. 2004, 17, 29. (j) Licini, G.; Prins, L. J.; Scrimin, P. Eur. J. Org. Chem. 2005, 969–977. (k) Goodman, C. M.; Choi, S.; Shandler, S.; DeGrado, W. F. Nat. Chem. Biol. 2007, 3, 252–262. (2) Hecht, S., Huc, I., Eds. Foldamers: Structure, Properties, and Applications; Wiley-VCH: Weinheim, 2007.
5498 J. Org. Chem. 2008, 73, 5498–5505
design materials that respond to environmental stimuli in predictable manners. We recently reported amphiphilic foldamers4 derived from cholic acid (Scheme 1).5 These so-called oligocholates fold into helical structures in nonpolar solvents (e.g., hexane/ethyl acetate or CCl4) containing a small amount of a polar solvent (e.g., DMSO or small alcohol). Intrastrand NH/OH hydrogen bonds are shown to be not important to the folding.4d Instead, a nanometer-sized hydrophilic cavity is created as the polar (3) For some recent examples of foldamers, see: (a) Rodriguez, J. M.; Hamilton, A. D. Angew. Chem., Int. Ed. 2007, 46, 8614–8617. (b) Dong, Z.; Yap, G. P. A.; Fox, J. M. J. Am. Chem. Soc. 2007, 129, 11850–11853. (c) Liu, S.; Zavalij, P. Y.; Lam, Y.-F.; Isaacs, L. J. Am. Chem. Soc. 2007, 129, 11232– 11241. (d) Kolomiets, E.; Berl, V.; Lehn, J.-M. Chem.sEur. J. 2007, 13, 5466– 5479. (e) Baruah, P. K.; Gonnade, R.; Rajamohanan, P. R.; Hofmann, H.-J.; Sanjayan, G. J. J. Org. Chem. 2007, 72, 5077–5084. (f) Price, J. L.; Horne, W. S.; Gellman, S. H. J. Am. Chem. Soc. 2007, 129, 6376–6377. (g) Smaldone, R. A.; Moore, J. S. J. Am. Chem. Soc. 2007, 129, 5444–5450. (h) Li, C.; Wang, G.-T.; Yi, H.-P.; Jiang, X.-K.; Li, Z.-T.; Wang, R.-X. Org. Lett. 2007, 9, 1797– 1800. (i) Shin, S. B. Y.; Yoo, B.; Todaro, L. J.; Kirshenbaum, K. J. Am. Chem. Soc. 2007, 129, 3218–3225. (j) Yashima, E.; Maeda, K. Macromolecules 2008, 41, 3–12. (4) (a) Zhao, Y.; Zhong, Z. J. Am. Chem. Soc. 2005, 127, 17894–17901. (b) Zhao, Y.; Zhong, Z. J. Am. Chem. Soc. 2006, 128, 9988–9989. (c) Zhao, Y.; Zhong, Z. Org. Lett. 2006, 8, 4715–4717. (d) Zhao, Y.; Zhong, Z.; Ryu, E.-H. J. Am. Chem. Soc. 2007, 129, 218–225. (e) Zhao, Y.; Zhong, Z. Org. Lett. 2007, 9, 2891–2894.
10.1021/jo800724j CCC: $40.75 2008 American Chemical Society Published on Web 06/24/2008
Folding of Oligocholates in Micelles SCHEME 1.
Cholic Acid and Oligocholate
hydroxyl groups of an oligocholate point inward and is solvated by the polar solvent preferentially.4 This preferential solvation allows the folded oligocholate to minimize the unfavorable solvophobic contact between its polar faces and the nonpolar solvent.4 Moreover, some of the polar solvent molecules now “happily” reside within a hydrophilic microenvironment instead of in the bulk, mostly nonpolar medium. Because the oligocholate relies on this preferential solvation to fold, unless stabilized by other interactions such as metal-ligand complexation,4b,e its folding requires the above mentioned special solvent mixtures. In this paper, we report the folding of the oligocholates within surfactant micelles. An interesting discovery is that surfactant micelles, as nanosized hydrophobic microenvironments dispersed in aqueous solution, can control the conformation of the oligocholate. A small, spherical micelle forces the oligocholate into the folded conformation, whereas an elongated micelle easily accommodates an unfolded oligocholate. Nearly all foldamers reported in recent years fold in homogeneous solutions and/or in the solid state.1–3 Although foldamers have been used to interact with lipid membranes,6 their folding within surfactants assemblies (micelles or membranes) has not been studied in detail.7 Importantly, surfactant micelles represent unique environments and are frequently used by biochemists (5) For some examples of supramolecular systems constructed from cholic acid, see: (a) Davis, A. P.; Bonar-Law, R. P.; Sanders, J. K. M. In ComprehensiVe Supramolecular Chemistry; Atwood, J. L., Davis, J. E. D., MacNicol, D. D., Vo¨gtle, F., Eds.; Elsevier: Oxford, 1996; Vol. 4, Chapter 7. (b) Li, Y.; Dias, J. R. Chem. ReV. 1997, 97, 283–304. (c) Maitra, U. Curr. Sci. 1996, 71, 617– 624. (d) Zhu, X. X.; Nichifor, M. Acc. Chem. Res. 2002, 35, 539–546. (e) Smith, B. D.; Lambert, T. N. Chem. Commun. 2003, 2261–2268. (f) Davis, A. P.; Joos, J.-B. Coord. Chem. ReV. 2003, 240, 143–156. (g) Virtanen, E.; Kolehmainen, E. Use of bile acids in pharmacological and supramolecular applications. Eur. J. Org. Chem. 2004, 3385–3399. (h) Zhao, Y. Curr. Opin. Colloid Interface Sci. 2007, 12, 92–97. (i) Burrows, C. J.; Sauter, R. A. J. Inclusion Phenom. 1987, 5, 117–121. (j) Janout, V.; Lanier, M.; Regen, S. L. J. Am. Chem. Soc. 1996, 118, 1573–1574. (k) Ariga, K.; Terasaka, Y.; Sakai, D.; Tsuji, H.; Kikuchi, J.-I. J. Am. Chem. Soc. 2000, 122, 7835–7836. (l) Werner, F.; Schneider, H.J. J. Inclusion Phenom. Macro. Chem. 2001, 41, 37–40. (m) Yoshino, N.; Satake, A.; Kobuke, Y. Angew. Chem., Int. Ed. 2001, 40, 457–459. (n) Janout, V.; Regen, S. L. J. Am. Chem. Soc. 2005, 127, 22–23. (6) For some examples of amphiphilic foldamers that interact with lipid bilayers, see: (a) Arnt, L.; Tew, G. N. J. Am. Chem. Soc. 2002, 124, 7664– 7665. (b) Liu, D.; Choi, S.; Chen, B.; Doerksen, R. J.; Clements, D. J.; Winkler, J. D.; Klein, M. L.; DeGrado, W. F. Angew. Chem., Int. Ed. 2004, 43, 1158– 1162. (c) Schmitt, M. A.; Weisblum, B.; Gellman, S. H. J. Am. Chem. Soc. 2004, 126, 6848–6849. (d) Stephens, O. M.; Kim, S.; Welch, B. D.; Hodsdon, M. E.; Kay, M. S.; Schepartz, A. J. Am. Chem. Soc. 2005, 127, 13126–13127. (e) Gillies, E. R.; Deiss, F.; Staedel, C.; Schmitter, J.-M.; Huc, I. Angew. Chem., Int. Ed. 2007, 46, 4081–4084.
to study how membrane-associated peptides/proteins behave in a membrane-like environment. 8 As the foldamer chemistry undergoes rapid development, studying the conformation of synthetic foldamers in surfactant assemblies should provide valuable insight into the folding of membrane proteins and enable new applications of foldamers. Results and Discussion Folding Models for the Oligocholates within SDS Micelles. According to our previous work, three units make up one turn in the helical conformer of the oligocholate.4a Interestingly, more than ten years ago, Sanders and co-workers reported that, when cyclic oligocholate esters were subjected to transesterification, the trimer was always the most thermodynamically favorable species.9 Although their cyclic oligocholates are connected by ester bonds and our linear cholate foldamers by amide, both Sanders’ work and ours suggest that the cholate backbone prefers trimeric periodicity. Because of the large size of the repeat unit (ca. 1.4 nm from head to tail) and the trimeric periodicity, the molecule changes its dimension rather dramatically during folding/unfolding. As shown by the molecular models of a cholate hexamer, the molecule can extend over several nanometers in length in the unfolded state but shrinks to 3.6 nm (E < 0.05) leaves no doubt for the unfolding of the oligocholate upon NaCl addition. Considering the dimension of the unfolded oligocholate and its hydrophobicity, it is reasonable to assume that rodlike micelles are formed around the unfolded foldamer. Another way to increase the micelle size (length) is to keep the salt concentration constant while increasing the SDS concentration.12 Indeed, when the concentration of NaCl is maintained at 100 mM and that of SDS is increased from 1 to 70 mM, oligomer 2 is observed to unfold also, as judged by the decrease of the acceptor emission (Figure 5a). This result is fully consistent with the “confinement effect”. Note that the acceptor emission of foldamer 2 is much stronger in the NaCl micellar solution than in water, particularly at low concentrations of SDS. For example, the emission intensity of dansyl in 2 is >200 in 1 mM SDS in 100 mM NaCl (Figure 5a, green trace) but is
