Hydration changes accompanying nucleic acid intercalation reactions:volumetric characterizations

Area of Science:

• Biophysical Chemistry
• Molecular Biology
• Drug Discovery

Background:

• Understanding drug-nucleic acid interactions is crucial for developing new therapeutics.
• Ethidium is a well-known intercalating agent used to study DNA and RNA structures.
• Macroscopic properties like volume and compressibility changes provide insights into molecular interactions.

Purpose of the Study:

• To quantify the volume (deltaV) and adiabatic compressibility (deltaK(S)) changes upon ethidium binding to various DNA and RNA duplexes and a triplex.
• To interpret these macroscopic changes in terms of differential hydration properties of nucleic acid structures.
• To estimate the entropic cost of hydration changes associated with ethidium intercalation.

Main Methods:

• High-precision ultrasonic velocimetry and densimetry at 25°C.
• Measurement of volume and adiabatic compressibility changes.
• Quantitative interpretation of macroscopic properties based on hydration models.

Main Results:

• Ethidium binding to poly(rA)poly(rU), poly(dAdT)poly(dAdT), poly(dGdC)poly(dGdC), poly(dIdC)poly(dIdC) duplexes, and poly(rU)poly(rA)poly(rU) triplex resulted in negative deltaV and deltaK(S).
• These changes were quantitatively linked to differential hydration of the nucleic acid structures in ligand-free and ligand-bound states.
• The entropic cost of intercalation-induced hydration changes for both nucleic acids and ethidium was estimated.

Conclusions:

• Hydration plays a vital role in modulating the energetics of drug-DNA binding.
• Accurate analysis and prediction of nucleic acid recognition energetics require careful consideration of hydration effects.
• The study provides a framework for understanding drug-nucleic acid interactions through biophysical measurements.