Unveiling the Intermolecular Interactions between Drug 5-Fluorouracil and Watson-Crick/Hoogsteen Base Pairs: A...

Area of Science:

• Computational Chemistry
• Biomolecular Interactions
• Drug-DNA Interactions

Background:

• 5-fluorouracil (5FU) is a widely used chemotherapy drug.
• Understanding drug-DNA interactions is crucial for drug design and efficacy.
• The binding modes of 5FU to DNA base pairs are not fully elucidated.

Purpose of the Study:

• To investigate the adsorption and binding mechanisms of 5FU on Watson-Crick (WC) and Hoogsteen (HT) DNA base pairs.
• To determine the thermodynamic stability and preferred binding geometries of 5FU-DNA complexes.
• To analyze the electronic properties and intermolecular interactions governing 5FU adsorption.

Main Methods:

• Dispersion-corrected Density Functional Theory (DFT) calculations were employed.
• Adsorption energies, binding energies, and thermochemistry were computed.
• Electron Density Difference (EDD), Molecular Electrostatic Potential (MESP), and Noncovalent Interaction (NCI) analyses were performed.

Main Results:

• 5FU exhibits a higher preference for binding to WC base pairs compared to HT base pairs.
• Adsorption energies are higher for 5FU on nucleobase pairs than on pristine nucleobases, indicating resistance to DNA cleavage.
• The formation of 5FU-DNA base pairs is enthalpy-driven, with stronger hydrogen bonding interactions stabilizing the complexes.

Conclusions:

• The study elucidates the preferential binding of 5FU to WC DNA base pairs through DFT calculations.
• The observed binding is thermodynamically favorable and stabilized by strong hydrogen bonds and electrostatic interactions.
• Findings suggest that 5FU adsorption is unlikely to induce DNA base pair cleavage, providing insights into its mechanism of action.