Approaches to Introduce Helical Structure in Cysteine-Containing Peptides with a Bimane Group.

Area of Science:

• Biochemistry
• Chemical Biology
• Structural Biology

Background:

• Peptide structure and stability are crucial for biological function.
• Estrogen Receptor alpha (ERα) targeted peptides are important in therapeutic strategies.
• Controlling peptide conformation is key to enhancing their efficacy.

Purpose of the Study:

• To investigate the impact of bimane-containing linkers on peptide structure.
• To explore the use of bimane as a tool for stabilizing helical conformations in peptides.
• To assess the influence of bimane modification on peptide interaction with Estrogen Receptor alpha.

Main Methods:

• Synthesis of bimane-modified peptides and macrocycles.
• Circular Dichroism (CD) and Nuclear Magnetic Resonance (NMR) spectroscopy for structural analysis.
• In silico modeling to study peptide-ERα interactions.

Main Results:

• The i-i+4 constrained peptide macrocycle adopted a 3₁₀-helical structure in solution.
• The peptide adopted an α-helical conformation upon interaction with the ERα coactivator recruitment surface (in silico).
• Bimane modification influenced peptide structure in a sequence-dependent manner, with aromatic residues enhancing helicity.

Conclusions:

• Bimane is a useful modification for influencing peptide structure, both in acyclic peptides and as a macrocyclic constraint.
• The conformational changes observed suggest potential for modulating peptide interactions with targets like ERα.
• Fluorescence properties of bimane are sensitive to peptide conformation, offering a potential readout for structural changes.