Halogen Bonding: A Powerful Tool for Modulation of Peptide Conformation

Area of Science:

• Biophysics
• Chemical Biology
• Structural Biology

Background:

• Halogen bonding is an underutilized weak chemical force, primarily applied in crystal engineering.
• Its potential in biopolymers for molecular recognition and drug discovery remains largely unexplored.
• Assessing weak forces in biologically relevant environments is crucial for understanding molecular interactions.

Purpose of the Study:

• To develop a peptide model system for quantitatively evaluating weak forces in a protein-like environment.
• To assess the conformational influence of a halogen bond between amino acid side chains.
• To demonstrate the technique's applicability for studying various weak secondary interactions.

Main Methods:

• Optimization of a peptide model system with a hydrogen bond-forming site.
• Quantitative evaluation of weak forces by measuring conformational modulation.
• Combined solution nuclear magnetic resonance (NMR) spectroscopy and computational analysis.

Main Results:

• A chlorine-centered halogen bond was successfully incorporated into a peptide system.
• The interstrand halogen bond demonstrated conformational stabilization of a β-hairpin foldamer.
• The stabilizing effect was comparable to that of an analogous hydrogen bond.

Conclusions:

• Halogen bonding can stabilize peptide/protein conformations in a biologically relevant context.
• This study provides the first quantification of a chlorine-centered halogen bond in a biologically relevant solution system.
• The findings highlight the potential of halogen bonding as a tool in drug discovery and molecular recognition.