Three dibenzofuran-based amino acid residues, namely 4-(2-aminoethyl)-6-dibenzofuranpropanoic acid (1), 4-(aminomethyl)-6-dibenzofuranethanoic acid (2), and 4-amino-6-dibenzofuranmethanoic acid (3), were prepared in order to compare their physical properties so as to further understand residue l's ability to nucleate antiparallel 3-sheet formation within small peptides in aqueous solution. FT-IR, variable temperature NMR, and an X-ray crystallography study reveal that amide analogs of 1 and 2 can adopt intramolecularly hydrogen bonded conformations in nonpolar solvents, whereas amides composed of residue 3 cannot. Spectroscopic studies reveal that linear heptapeptides containing 1 are capable of adopting a dynamic antiparallel 3-sheet structure in aqueous solution, whereas residues 2 and 3 are incapable of nucleating a 3-sheet structure in an otherwise identical peptide sequence. The efficacy of residue 1 as a 3-sheet nucleator appears to result from a 15-membered ring intramolecularly hydrogen-bonded hydrophobic cluster conformation which serves as a partial 3-sheet template enabling neighboring residues to be added to the growing sheet with a favorable equilibrium constant. The hydrophobic cluster conformation in these heptapeptides is stabilized by (S-Sheet Formation via Dibenzofuran-Based Amino Acids acid sequence which will adopt a partial /8-sheet structure capable of nucleating a /8-sheet,* 2 **S.*'7 we set out to design an amino acid that will stabilize a partial /8-sheet structure and thus nucleate /3-sheet formation in aqueous solution.8The concept of introducing a conformationally rigid molecule into a peptide to stabilize a single conformation was established by Hirschmann, Veber, Freidinger, Nutt, and their colleagues at Merck.9 Since then and previous to our efforts, several elegant dipeptide and related 8-turn mimetics have been prepared either to control the conformation of peptides and/or as potential pharmaceuticals.10 The ability to design a molecular fragment which nucleates 8-sheet formation was first demonstrated by Kemp by employing the epindolidione nucleus. When the epindolidione ring system is incorporated into an a-amino acid sequence, it serves as an artificial 8-strand and mediates sheet formation via hydrogen bonding between the epindolidione skeleton and the covalently attached peptide chain.10'0'11 The goal of the work described here is to develop an amino acid that is a dipeptide mimetic of the i + 1 and i + 2 residues of a 8-turn in an effort to nucleate 8-sheet folding without significantly perturbing the resulting antiparallel 8-sheet structure. Protein

The helicity in water has been determined for several series of alanine-rich peptides that contain single lysine residues and that are N-terminally linked to a helixinducing and reporting template termed Ac-Hel1. The helixpropagating constant for alanine (SAla value) Ac-Hell (Fig. 1C), and these conjugates can be used to distinguish stabilizing effects arising from initiation of a helix from those attributable to its propagation (10-13). As a capping group at the N terminus of a polypeptide, Ac-Hell acts as a helix initiator, and the stability of the helices it initiates within the peptide is proportional to the trans/cis value (t/c) of Ac-Hell, measurable as a ratio of intensities of 'H NMR resonances assigned to s-trans and s-cis conformers of its acetamido function (12, 13). For a particular amino acid residue the helix propagation constant s measures its tendency to join a linked, preexisting helix (14), and for a series of template-linked peptides such as Ac-Hel,-Xn-NH2 or Ac-Hell-Y-Xn-NH2, where Y represents any linking peptide, an average sx can be assigned to amino acids in the X, region from the curvature of a plot of tic vs. n (10, 11, 13). Although one can argue for differences between the helices of this study, propagated unidirectionally in the N-to-C direction, and helices that are propagated from the C terminus or propagated bidirectionally, until evidence to the contrary is forthcoming, it is simpler to view propagation effects measured at a distance from the initiation site as insensitive to the site or nature of the initiation.A lysine residue at the C terminus or in the core of an a-helix may adopt the solvent-exposed conformation shown in Fig. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. (Fig. 1B). In the latter, lysine may stabilize the helix through a position-dependent electrostatic interaction between the NH3 ion and the helix dipole (9,15,19,20), through a ,r-type hydrogen bond between the NH3 ion and a carbonyl oxygen of the helix core, and through hydrophobic contacts between the hydrocarbon portion of the lysine side chain and the helix core (13,21). If lysine-bearing helices are significantly stabilized by charge-dipole interactions, their helicity is expected to be sensitive to the position of the lysine along the peptide sequence. Moreover, for conformations like that of Fig. 1B, the stabilization attributable to hydrophobic contacts, chargedipole effects, and Tr-hydrogen bonding must change if the length of the lysine side chain is shortened.We have explored this issue in three ways. The tic values for template-peptide conjugates of structure Ac-Hell-Alan-LysAlam-NH2 have been used to assign SAla and to measure the sensitivity of SLys to position. The t/c changes that result when lysine is replaced by amino acid analogs bearing shorter methyleneammonium functions -(CH2)n-NH3, n = 1-3 have been used to pro...

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