Solution and solid state conformational preferences of a family of cyclic disulphide bridged tetrapeptides.

A set of cyclic tetrapeptides of the general form cyclo (Boc-Cys-Pro-X-Cys-OMe) with X being L-/D-Ala, L-/D-Val, and L-/D-Trp was synthesized. These peptides serve as model systems for structure elucidation in solution and feature a variety of structural motifs - namely a ß-turn with intramolecular hydrogen bonding interactions, cis/trans isomerism, and a disulphide bond. In this work, we performed a comprehensive structural analysis focussing on their ß-turn conformational preferences using NMR, VCD, and Raman spectroscopy. Our results provide evidence for a strong influence of a single stereocenter on the structures of the peptides whereas solvent polarity does not significantly affect them. Additionally, the solid state conformational preferences were studied by crystal structure analysis. Overall, a general trend for the conformational preferences of this set of peptides can be concluded from the results of the complementary investigations.

Solvent-induced conformational changes in cyclic peptides: a vibrational circular dichroism study.

The three-dimensional structure of a peptide is strongly influenced by its solvent environment. In the present study, we study three cyclic tetrapeptides which serve as model peptides for ß-turns. They are of the general structure cyclo(Boc-Cys-Pro-X-Cys-OMe) with the amino acid X being either glycine (1), or L- or D-leucine (L- or D-2). Using vibrational circular dichroism (VCD) spectroscopy, we confirm previous NMR results which showed that D-2 adopts predominantly a ßII turn structure in apolar and polar solvents. Our results for L-2 indicate a preference for a ßI structure over ßII. With increasing solvent polarity, the preference for 1 is shifted from ßII towards ßI. This conformational change goes along with the breaking of an intramolecular hydrogen bond which stabilizes the ßII conformation. Instead, a hydrogen bond with a solvent molecule can stabilize the ßI turn conformation.

Conformation and dynamics of a cyclic disulfide-bridged peptide: effects of temperature and solvent.

The cyclic disulfide-bridged tetrapeptide cyclo(Boc-Cys-Pro-Gly-Cys-OMe) (1) was designed as a model for the study of solvent-driven conformational changes in peptides. The three-dimensional structure and dynamics of 1 were studied using a variety of experimental and computational techniques. The crystal structure of 1 reveals a ß-turn stabilized by a hydrogen bond between the two cysteine residues. In solution, the UV-CD and NMR analysis of 1 suggest a ß-turn II conformation, stable up to 60 °C. The characteristic NMR (13)C shifts of the Cß and Cγ atoms of proline show that the peptide adopts exclusively the energetically favored trans conformation of the peptidyl-prolyl bond. The combination of IR spectroscopy with Car-Parrinello MD simulations and DFT calculations allowed us to assign the absorptions in the amide I region to the individual amino acids. The NH group of Gly, which as hydrogen bond donor competes with the NH group of Cys4 for the carbonyl oxygen atom of Cys1 as hydrogen bond acceptor, plays a relevant role for the structure and spectroscopic properties of the peptide. Since Gly is more exposed to the solvent, its hydrogen-bonding capability can be partially blocked by external solvent molecules in solution or by a second peptide molecule in the crystal. Furthermore, the presence of only one molecule of acetonitrile is sufficient to change the preferred conformation of 1, and even in acetonitrile solution the simulations suggest that on average only one solvent molecule strongly interacts with the cyclic core of the peptide.

Stereochemistry rules: a single stereocenter changes the conformation of a cyclic tetrapeptide.

Two novel cyclo(Boc-Cys-Pro-Leu-Cys-OMe) peptides 1 and 2 containing the enantiomeric amino acids d-Leu and l-Leu, respectively, were synthesized to investigate the effect of chiral centers on peptide conformations. By combining a variety of experimental techniques (X-ray crystallography, 2D NMR spectroscopy, temperature-dependent (1)H NMR and IR spectroscopy, and UV-CD spectroscopy) with replica exchange molecular dynamics (REMD) techniques and quantum mechanics/molecular dynamics (QM/MM) calculations, we establish that the stereochemistry of just one residue can noticeably influence the properties of the whole peptide and rationalize the origins of this effect, with potential implications for the rational design of peptides of chemical and biological relevance.