Molecular dynamics study on the binding of S- and R-ofloxacin to [d(ATAGCGCTAT)]2 oligonucleotide: Effects of protonation states

Abstract

The energies for the complex formation between the S- and R-enantiomers of ofloxacin with the [d(ATAGCGCTAT)]2 were calculated using the molecular dynamics (MD) method. The 12 initial structures that were investigated in this work included were three ofloxacin: neutrals; zwitterions; and the protonated species, for both the S- and R-enantiomers, each with two starting positions intercalative and minor groove. The four final structures with the most favorable free energies from the MD calculations consisted of two categories namely, partial intercalative and the minor groove binding model. In the intercalative model that is found for the protonated species, the molecular plane of both the S- and R-ofloxacin is inserted between two GC base-pairs with the protonated piperazine ring and the methyl group of the oxazine ring is exposed to the minor groove. The binding energy of the S-ofloxacin in this model is slightly more favorable than R-ofloxacin. Conversely, even as it began with an initial intercalative structure, the neutral ofloxacin species is bound within the minor groove, whereby the molecular plane of ofloxacin tilts between 60-70° with respect to the DNA helical axis. Two hydrogen bonds are possible for this groove binding model. Finally, the free energy of the zwitterionic ofloxacin is less favorable than that obtained from neutral and protonated species.