Ab Initio and DFT Calculations of Increasingly Complex Models of Ligand-Nucleic Acid Binding

Abstract

This work focuses on the binding of a model intercalant (indole) between the pairings of the four DNA bases to ascertain the most likely location of the binding of a carcinogen or chemotherapeutic drug. This knowledge will aid in the design and targeting of future chemotherapy drugs. Ten complexes (DNA base-intercalant-DNA base) were optimized into free structures and sandwich structures using MP2/6-31g. Interaction energies were computed for these complexes using the MP2 and DFT methods with the 6-31+g* and 6-311+g* basis sets. Comparison of the stability of the free structures to the stability of the sandwich structures allowed estimation of the distorting force acting on that segment of DNA. A short strand of DNA with an intercalant bound in between two bases was then studied using the ONIOM method. MP2 and DFT methods were used to model the interactions between the bases and the intercalant, while AM1 was used to model the DNA backbone. These calculations are crucial because the manner in which DNA distorts depends heavily on the backbone and the presence of the neighboring DNA bases. Finally, models of the intercalant bound between pairs of two bases in double- stranded DNA were modeled using ONIOM. The double-stranded results show interactions around -40 kcal/mol for all pairings of DNA bases, and this result is consistent with the single-stranded DNA and free nucleic acid base models.