Solvent-Enhanced Conformational Flexibility of Cyclic Tetrapeptides

Abstract

Solvent and temperature can affect the structural properties of cyclic peptides by controlling their flexibility. Here, we investigate two cyclic peptides, featuring beta turns. Using temperature-dependent NMR and FT-IR, we observed a pronounced temperature effect on the conformation of the cyclic peptide D-1 in CHCl₃ but a much smaller effect in CH₃ CN. Almost no effect was observed for its diastereomer L-1 within a similar temperature range and using the same solvents. With the aid of Replica Exchange Molecular Dynamics simulations and Quantum Mechanics/Molecular Mechanics calculations, we were able to explain this behavior based on the increased flexibility of D-1 (in CHCl₃ ) in terms of intramolecular hydrogen bonding. The largest temperature dependence is observed for D-1 in CHCl₃ , while the temperature effect is less pronounced for L-1 in CHCl₃ and for both peptides in CH₃ CN. This work provides new insights into the role of the environment and temperature on the conformations of cyclic peptides.

Keywords: IR spectroscopy; NMR spectroscopy; Quantum Mechanics/Molecular Mechanics; Replica Exchange Molecular Dynamics; cyclic peptides.