PUB - Publikationen an der Universität Bielefeld

beta-Amino acids with side chains at C-2 and/or at C-3 are of growing interest in drug design, as they may induce astonishing and unusual peptide conformations. Therefore it is of eminent importance to gather information on the consequences of beta-amino acid incorporation on the three-dimensional structure of a peptide. This paper describes the synthesis and conformational analysis of cyclic penta- and hexapeptides comprising either (S)-Pro or (S)-beta-Hpro. The conformational influence of the beta-homoproline building block was analyzed by the combined application of CD, FT-IR and NMR. While the CD spectra of the proline containing peptides indicate the presence of inverse gamma-turns and beta II-turns, the CD spectra of the beta-homoamino acid analogs are dominated by an unprecedented negative band near 205 nm associated with a pseudo-beta-turn (Psi beta) or pseudo-gamma-turn (Psi gamma). These results were confirmed by FT-IR spectroscopy, which also indicates the formation of two internal hydrogen bonds in the cyclic peptides containing the beta-homoproline. The conformations of the beta-homoproline containing pentapeptides were additionally determined by NMR in combination with MD simulations in two different solvents. The conformation in trifluoroethanol (TFE) is characterized by a bifurcated hydrogen bond stabilizing a pseudo-gamma-turn with beta-homoproline in the central position, nested with a pseudo-beta-turn with beta-homoproline in the i + l position. The combined CD/FT-IR studies clearly show that the replacement of proline by beta-homoproline gives rise to a more flexible peptide backbone, and CD spectroscopy hints towards the presence of pseudo-beta- or pseudo-gamma-turns.