Computational study of the interaction of proflavine with d(ATATATATAT)2 and d(GCGCGCGCGC)2

The interaction of proflavine (PR) with two B-DNA decamers of alternating AT and GC sequence, called [deca(dG-dC)]2 and [deca(dA-dT)]2, respectively, was computationally investigated by the ONIOM method, exploiting a three-layer QM/QM/MM hybrid approach. The highest level QM method was applied to the model system, which comprises the intercalation site (5th and 6th base pairs) and the inserted PR molecule. The connecting sugar phosphate backbone was added in the medium layer region. Both higher and medium level layers, differing in the size of the basis set used, were treated by the DFT MPWB1K functional. The full system in the lower layer was described by the empirical AMBER force field. The calculated values of the interaction energy of PR with [deca(dG-dC)]2 and [deca(dA-dT)]2, as well as with the dinucleotides d(GpC)2, and d(ApT)2, the latter considered either in vacuo and in the mimicked water solvent, support for a static higher affinity toward G-C compared to the A-T DNA base sequences, in agreement with structural results from crystallographic studies. Furthermore, the different structural characteristics of the [deca(dG-dC)]2/PR complex compared to those of the [deca(dA-dT)]2/PR, furnish a possible interpretation of apparently controversial experimental thermodynamic data, explained in terms of two possible modes of non-covalent binding of ligands with DNA, namely intercalation and external binding, respectively.