Accommodation of r-Substituted Residues in the -Peptide 12-Helix: Expanding the Range of Substitution Patterns Available to a Foldamer Scaffold Jin-Seong Park, ² Hee-Seung Lee, ‡ Jonathan R. Lai, § Byeong Moon Kim, ² and Samuel H. Gellman , * ,‡,§ School of Chemistry, College of Natural Sciences, Seoul National UniVersity, Seoul 151-742, Korea, Department of Chemistry, UniVersity of Wisconsin, Madison, Wisconsin 53706, and Graduate Program in Biophysics, UniVersity of Wisconsin, Madison, Wisconsin 53706 Received January 15, 2003; E-mail: gellman@chem.wisc.edu Abstract: -Amino acid oligomers composed exclusively of homochiral trans-2-aminocyclopentanecarboxylic acid (ACPC) residues and/or related pyrrolidine-based residues are known to favor a specific helical secondary structure that is defined by 12-membered ring CdO(i)- -H-N(i+3) hydrogen bonds (“12-helix”). The 12-helix is structurally similar to the familiar R-helix and therefore represents a source of potential R-helix-mimics. The 12-helix will be most useful in this regard if this conformational scaffold can be employed to arrange specific sets of protein-like side chains in space. Here we examine whether the 12-helix tolerates insertion of acyclic -amino acid residues bearing a substituent in the R-position (“ 2 -residues”). Seventeen homologous -peptide heptamers have been prepared in which one to four  2 -residues reside among ACPC and/or pyrrolidine residues. Circular dichroism comparisons suggest that  2 -residues have a lower 12- helical propensity than do residues preorganized by a five-membered ring, as expected, but that -peptides containing  2 -residues at one or two of the seven positions retain a significant preference for 12-helix formation. These results indicate that a limited number of  2 -residues can be used to introduce side chains at specific positions along the surface of a 12-helix. Introduction Interest in foldamers 1 (oligomers with well-defined folding propensities) is expanding in scope from control of molecular shape to control of function. 2 Engineering specific activities into foldamers is an attractive prospect because three-dimensional relationships among side chains in the folded conformation can be predicted on the basis of sequential relationships among monomer residues. The ability to design foldamers that perform specific tasks requires development of strategies for introducing side chains at defined positions along a given foldamer backbone. As the backbones of residues grow larger, there is an increase in the number of positions within each residue at which side chains may be attached. -Peptides, oligomers of -amino acids, are among the most thoroughly studied unnatural foldamers to date. 3 The three types of regular secondary structure observed in R-amino acid peptides and proteins, reverse turn, sheet, and helix, have also been documented among -peptides. -Amino acids have two carbon atoms between the amino and carboxyl groups, which leads to a larger set of possible substitution patterns than is available for R-amino acids. Variation in residue substitution enables one to impose stronger and more diverse conformational propensities among -peptides than are possible among R-peptides. 3 For example, only two types of internally hydrogen bonded helix are commonly observed among R-peptides, the R-helix (13- membered ring CdO- -H-N hydrogen bonds) and the 3 10 -helix (10-membered ring hydrogen bonds). The R-helix seems intrinsically more favorable for most proteinogenic R-amino acid residues, but the factors that control helix preference among R-peptides are subtle. 4 In contrast, four internally hydrogen bonded helices have been identified to date among -peptides. These helices are named according to their internal hydrogen ² Seoul National University. ‡ Department of Chemistry, University of Wisconsin, Madison. § Graduate Program in Biophysics, University of Wisconsin, Madison. (1) (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173. (b) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S. Chem. ReV. 2001, 101, 3893. (2) (a) Werder, M.; Hausre, H.; Abele, S.; Seebach, D. HelV. Chim. Acta 1999, 82, 1774. (b) Hamuro, Y.; Schneider, J. P.; DeGrado, W. F. J. Am. Chem. Soc. 1999, 121, 12200. (c) Prince, R. B.; Barnes, S. A.; Moore, J. S. J. Am. Chem. Soc. 2000, 122, 2758. (d) Porter, E. A.; Wang, X.; Lee, H.-S.; Weisblum, B.; Gellman, S. H. Nature 2000, 404, 565. 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