Drug binding disrupts chiral water structures in the DNA first hydration shell

Area of Science:

• Biophysics
• Chemical Physics
• Molecular Biology

Background:

• Understanding DNA hydration is crucial for DNA biology and drug development.
• Probing *in situ* DNA hydration changes during molecular interactions is challenging.

Purpose of the Study:

• To investigate changes in DNA hydration structures upon drug binding using chiral-selective vibrational sum frequency generation spectroscopy (chiral SFG).
• To elucidate the role of water in the site-specific binding of netropsin to DNA.

Main Methods:

• Combined experimental and computational approach utilizing chiral SFG spectroscopy.
• Analysis of spectral changes to detect water displacement and differentiate hydrogen-bonding states.

Main Results:

• Chiral SFG successfully detected water displacement from the DNA minor groove upon netropsin binding.
• The technique distinguished between weakly and strongly hydrogen-bonded water molecules.
• Netropsin preferentially displaced strongly hydrogen-bonded water associated with thymine carbonyl groups.

Conclusions:

• Chiral SFG offers mechanistic insights into DNA hydration dynamics during drug interactions.
• Water molecules play a significant role in modulating the site-specificity of drug binding to DNA.
• The findings hold promise for advancing DNA-targeted drug development.