Beta-alanine containing cyclic peptides with turned structure: the "pseudo type II beta-turn." VI

Area of Science:

• Peptide Chemistry
• Structural Biology
• Computational Chemistry

Background:

• Cyclic peptides exhibit diverse biological activities.
• Understanding peptide conformation is crucial for drug design.
• The specific structure of cyclo-(L-Pro-L-Phe-beta-Ala)2 was previously uncharacterized.

Purpose of the Study:

• To synthesize and characterize the cyclic hexapeptide cyclo-(L-Pro-L-Phe-beta-Ala)2.
• To elucidate its conformational behavior in both solid and solution states.
• To investigate the impact of peptide bond configuration on secondary structure.

Main Methods:

• Classical solution-phase peptide synthesis.
• Cyclization using N,N-dicyclohexyl-carbodiimide.
• Single crystal X-ray diffraction analysis.
• Nuclear Magnetic Resonance (NMR) spectroscopy.
• Restrained molecular dynamics simulations.

Main Results:

• Successful synthesis and purification of cyclo-(L-Pro-L-Phe-beta-Ala)2.
• X-ray analysis revealed two distinct conformations in the solid state, with one trans and one cis beta-Ala-L-Pro peptide bond.
• NMR and simulations showed a mixture of conformations in solution, including a C2-symmetric form and one similar to the solid state.
• Pro-Phe segments consistently adopted angles resembling type II beta-turns.
• A novel 'pseudo type II beta-turn' structure was identified in conformations with a cis beta-Ala-Pro bond.

Conclusions:

• The cyclic hexapeptide cyclo-(L-Pro-L-Phe-beta-Ala)2 exhibits significant conformational flexibility.
• Solid-state and solution conformations differ, influenced by peptide bond configurations (cis/trans).
• The study introduces a new structural motif, the 'pseudo type II beta-turn', expanding conformational possibilities in cyclic peptides.