Probing Weak Halogen Bonding in Aqueous Solution

Area of Science:

• Chemical Physics
• Biophysical Chemistry
• Structural Biology

Background:

• Noncovalent interactions are fundamental to chemistry and biology, dictating molecular structure, binding affinities, and reaction mechanisms.
• Characterizing weak noncovalent forces, like halogen bonds, in aqueous solutions is challenging due to competing solvent interactions.
• Weak interactions are critical in biological processes and drug discovery, necessitating robust analytical methods.

Purpose of the Study:

• To develop and demonstrate a strategy for characterizing weak noncovalent interactions, specifically halogen bonding, in dilute aqueous solution.
• To quantify the relative strength and geometry of iodine- and bromine-centered halogen bonds using NMR spectroscopy.
• To provide a versatile methodology for assessing various weak interactions in biologically relevant solvents.

Main Methods:

• Utilized Nuclear Magnetic Resonance (NMR) spectroscopy, including NOE- and J-coupling-based ensemble analysis, to quantify the population of a stabilized β-hairpin motif.
• Employed 1H-13C residual dipolar couplings to determine the geometry and orientation of halogen bonds.
• Corroborated experimental findings with Density Functional Theory (DFT) calculations.

Main Results:

• Successfully characterized the relative strengths of weak halogen bonds involving iodine and bromine.
• Determined the geometric parameters of halogen bonds in aqueous solution.
• Demonstrated the stabilization effect of halogen bonds on a β-hairpin motif.

Conclusions:

• Presented a novel NMR-based strategy for the detailed experimental characterization of halogen bonding in aqueous solution.
• The methodology is transferable for assessing other weak noncovalent interactions in water, crucial for drug discovery.
• This work provides a foundation for understanding and manipulating weak interactions in biological systems.