Abstract
β-Amino acids with side chains at C2 and/or at C3 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 β-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)-β-Hpro. The conformational influence of the β-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 γ-turns and βII-turns, the CD spectra of the β-homoamino acid analogs are dominated by an unprecedented negative band near 205 nm associated with a pseudo-β-turn (Ψβ) or pseudo-γ-turn (Ψγ). These results were confirmed by FT-IR spectroscopy, which also indicates the formation of two internal hydrogen bonds in the cyclic peptides containing the β-homoproline. The conformations of the β-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-γ-turn with β-homoproline in the central position, nested with a pseudo-β-turn with β-homoproline in the i+1 position. The combined CD/FT-IR studies clearly show that the replacement of proline by β-homoproline gives rise to a more flexible peptide backbone, and CD spectroscopy hints towards the presence of pseudo-β- or pseudo-γ-turns.
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This project was supported by Deutsche Forschungsgemeinschaft (Germany, SFB 549 Macromolecular Processing and Signalling in the Extracellular Matrix), Deutscher Akademischer Austauschdienst (PPP), OTKA (Hungary, projects number T037719 and T 047186), and the Fonds der Chemischen Industrie (Frankfurt, Germany).
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Malešević, M., Majer, Z., Vass, E. et al. Spectroscopic Detection of Pseudo-Turns in Homodetic Cyclic Penta- and Hexapeptides Comprising β-Homoproline. Int J Pept Res Ther 12, 165–177 (2006). https://doi.org/10.1007/s10989-006-9013-8
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DOI: https://doi.org/10.1007/s10989-006-9013-8