Enthalpy-entropy contribution to carcinogen-induced DNA conformational heterogeneity

Area of Science:

• Molecular Biology
• Chemical Carcinogenesis
• Structural Biology

Background:

• DNA adduct formation by aromatic amines is a key step in environmental carcinogenesis.
• Aromatic amine DNA adducts exist in an equilibrium between major groove (B) and base-displaced stacked (S) conformations.
• Factors governing this conformational heterogeneity are not well understood.

Purpose of the Study:

• To investigate the thermodynamic and kinetic factors controlling the B/S conformational equilibrium of DNA adducts.
• To elucidate the role of enthalpy and entropy in governing DNA adduct conformation.
• To understand the structural basis of environmental carcinogenesis initiation.

Main Methods:

• Extensive calorimetry, Nuclear Magnetic Resonance (NMR), and Circular Dichroism (CD) studies.
• Analysis of model DNA lesions induced by fluorinated 2-aminofluorene (FAF) and 4-aminobiphenyl (FABP).
• van't Hoff analysis of dynamic (19)F NMR data to determine thermodynamic parameters.

Main Results:

• Significant differences in enthalpy-entropy compensation were observed between FABP and FAF adducts.
• FABP adducts exclusively adopt the B conformer with minimal thermodynamic changes.
• FAF adducts exist as a mixture of B and S conformers, driven by large enthalpy-entropy compensation.
• Favorable entropy of the S conformer over the B conformer dictates the S/B population ratio at physiological temperatures.

Conclusions:

• Conformational heterogeneity of DNA adducts is governed by a complex interplay of enthalpy and entropy.
• Entropy plays a crucial role in determining the population of different DNA adduct conformations.
• Understanding these thermodynamic principles provides insight into the mechanisms of aromatic amine-induced carcinogenesis.