Molecular dynamics simulations were used to investigate the interaction of DB818 with the DNA oligonucleotide d[CGCGAATTCGCG]2. A 5 ns MD calculation was performed to study the DB818-DNA complex and the results indicated that DB818 was inserted in the minor groove of DNA, binding to the region of duplex AATTC bases. The enhanced binding of DB818 to DNA is primary due to a more favorable curvature contribution and matches well the DNA minor groove topology. The bifurcated pair of H-bonds was formed between nitrogen atom of the benzimidazole ring and oxygen atoms of the thymine 7 and thymine 19, and other two specific H-bonds were formed between nitrogen atom of the amidinium group and oxygen atoms of thymine 20 and cytosine 9. Furthermore, the binding free energy of DB293-DNA and DB818-DNA complexes was calculated with MM_PBSA methods, and all of results were consistent with the literature data. Thermodynamics analysis showed that the enhanced binding of DB818 to AATT was due to much lager entropy and less enthalpy contribution. Molecular dynamics studies complement the structural analysis and offer a clear picture of the complex, providing the theoretical guidance for the design of biologically active minor groove agents.

Key words: minor groove binding, DB818, DNA, molecular dynamics simulation, free energy analysis