Methylene blue binding to DNA with alternating GC base sequence:: A modeling study

Photoactive methylene blue is one of the most efficient singlet oxygen generating dyes. It binds to DNA and induces photosensitized reactions which can be used for sequence-specific cleavage of the DNA backbone. Photophysical data obtained for methylene blue in complexes with DNA indicate different binding modes of the dye depending on base sequences. In this study, the binding of methylene blue to a double-stranded decamer with an alternating GC sequence has been investigated by structural modeling and force field based energy calculations. Solvation and desolvation effects have been treated using an electrostatic continuum model. For each of the three possible binding modes (intercalation and minor and major groove binding), a search of the configurational space resulted in six model structures which were selected by the criterion of lowest total energies. The differences of estimated energies are only a few kilocalories per mole, but suggest a preference for symmetric intercalation at the 5'-CpG-3' or 5'-GpC-3' steps. Asymmetric intercalation and minor and major groove binding appear to be less favorable. This result is compatible with published circular dichroism data. An energetic analysis of the model structures gives detailed insight into the interactions involved in the stabilization of the complex and clearly shows the importance of solvent contributions in selecting the most probable structure from an ensemble of structural alternatives.