Solvent‐Enhanced Conformational Flexibility of Cyclic Tetrapeptides

• Published in: Chemphyschem 2019-07, Vol.20 (13), p.1664-1670
• Main Authors: Berger, Nadja, Wollny, Laura J. B., Sokkar, Pandian, Mittal, Sumit, Mieres‐Perez, Joel, Stoll, Raphael, Sander, Wolfram, Sanchez‐Garcia, Elsa
• Format: Article
• Language: English
• Subjects: Acetonitriles - chemistry; Chloroform; Chloroform - chemistry; cyclic peptides; Flexibility; Hydrogen Bonding; IR spectroscopy; Magnetic Resonance Spectroscopy; Molecular dynamics; Molecular Dynamics Simulation; NMR; NMR spectroscopy; Nuclear magnetic resonance; Peptides; Peptides, Cyclic - chemistry; Pliability; Protein Conformation; Quantum mechanics; Quantum Mechanics/Molecular Mechanics; Quantum Theory; Replica Exchange Molecular Dynamics; Solvents; Solvents - chemistry; Spectroscopy, Fourier Transform Infrared; Temperature; Temperature dependence; Temperature effects
• ISSN: 1439-4235; 1439-7641
• DOI: 10.1002/cphc.201900345

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 CH3CN. 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 CH3CN. This work provides new insights into the role of the environment and temperature on the conformations of cyclic peptides. Tuning tetrapeptide conformation: A multi‐resolution computational approach was used for the interpretation of the temperature‐dependent NMR and FT‐IR spectra of two cyclic tetrapeptides. We found that the combination of three factors: temperature, solvent, and configuration of the amino acid in position 4 allows tuning the conformational preferences of cyclic tetrapeptides, with potential implications for the targeted design of structures with β‐turn motifs.