An Improved Turn Structure for Inducing β-Hairpin Formation in Peptides

Area of Science:

• Peptide Chemistry
• Structural Biology
• Biochemistry

Background:

• Beta-hairpins are common protein structures, but controlling their formation in short peptides remains challenging.
• Existing methods lack sequence-independent tools to reliably induce beta-hairpin conformations.

Purpose of the Study:

• To develop a novel peptide building block that reliably induces beta-hairpin formation.
• To synthesize and characterize a new beta-turn template, delta-linked gamma(R)-methyl-ornithine (δMeOrn).

Main Methods:

• Developed a synthesis for protected δMeOrn suitable for Fmoc-based solid-phase peptide synthesis.
• Utilized X-ray crystallography to confirm the folded structure of the δMeOrn turn unit in a macrocyclic peptide.
• Employed Circular Dichroism (CD) and Nuclear Magnetic Resonance (NMR) spectroscopy for comparative analysis.

Main Results:

• Successfully synthesized gram quantities of the Nα-Boc-Nδ-Fmoc-γ(R)-methyl-ornithine building block.
• X-ray crystallography confirmed the desired folded conformation of the δMeOrn turn in a macrocyclic beta-hairpin.
• Comparative spectroscopy demonstrated that δMeOrn is superior to δOrn and comparable to d-Pro-Gly as a turn template.

Conclusions:

• δMeOrn serves as an effective beta-turn template for inducing beta-hairpin conformations in peptides.
• The developed synthesis provides a versatile building block for peptide engineering.
• This offers a promising new strategy for designing peptides with specific structural and functional properties.