Solvent-mediated conformational transition in beta-alanine containing cyclic peptides. VIII

Area of Science:

• Structural biology
• Computational chemistry
• Biophysics

Background:

• Cyclic peptides possess unique conformational properties.
• Understanding peptide structure in solution is crucial for drug design.
• Cyclo-(Pro-Phe-Phe-beta-Ala-beta-Ala) is a model system for conformational studies.

Purpose of the Study:

• To elucidate the solution-state conformations of cyclo-(Pro-Phe-Phe-beta-Ala-beta-Ala).
• To investigate the influence of different solvents (CD3CN, DMSO) on peptide conformation.
• To explore cis-trans isomerism around the beta-Ala5-Pro1 peptide bond.

Main Methods:

• Nuclear Magnetic Resonance (NMR) spectroscopy, including rotating frame nuclear Overhauser effect (ROESY) and homonuclear coupling constants.
• Restrained molecular dynamics (MD) simulations in vacuo.
• Conformational analysis in CD3CN and DMSO solutions, and solvent mixtures.

Main Results:

• The peptide exists as two slowly interconverting conformers in both CD3CN and DMSO, driven by cis-trans isomerism at the beta-Ala5-Pro1 bond.
• In CD3CN, one conformer resembles the solid-state structure; the other (all-trans) features an intramolecular hydrogen bond stabilizing C10 and C13 rings.
• In DMSO, the trans isomer shows some similarity to the CD3CN conformer, while the cis isomer differs from the solid-state structure.

Conclusions:

• Solvent environment significantly impacts the conformational landscape of cyclo-(Pro-Phe-Phe-beta-Ala-beta-Ala).
• Intramolecular hydrogen bonding plays a key role in stabilizing specific conformations in non-polar solvents.
• The study provides insights into the conformational flexibility and solvent-dependent behavior of cyclic peptides.