Molecular Dynamics Simulations of the Bis-Intercalated Complexes of Ditercalinium and Flexi-Di with the Hexanucleotide d(GCGCGC)2: Theoretical Analysis of the Interaction and Rationale for the Sequence Binding Specificity

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Abstract
The X-ray crystal structures of the complexes of ditercalinium and Flexi-Di with d(CGCG)2 have been studied by computational chemistry methods in an attempt to rationalize their distinct structural features. In addition, the complexes of these two bisintercalating drugs with d(GCGCGC)2 have been modeled and subjected to 0.5 ns of molecular dynamics simulations in explicit solvent with the aim of evaluating the relative importance of hydrogen bonding and stacking interactions in the sequence binding specificity of these compounds. According to our calculations, the electrostatic term is attractive for the stacking interactions between the pyridocarbazole chromophores of these drugs and the base pairs that make up the sandwiched GpC step. On the contrary, this energy term is repulsive for the base pairs that make up the boundaries of the bisintercalation site. This differential electrostatic binding energy component, which is shown to have a strong orientational dependence, could lie at the origin of the observed binding preferences of these drugs. In addition, both the Lennard−Jones and the electrostatic energy terms contribute to stabilizing the underwound central GpC step. The attractive electrostatic interactions between the linkers and the major groove are in concert with the stacking specificities for the sandwiched GpC step, which is thus very effectively stapled by the drugs. The hydrogen-bonding potential of the linkers, however, appears to be reduced in an aqueous medium due to competing interactions with water. Binding of either ditercalinium or Flexi-Di to d(GCGCGC)2 appears to favor the A-type conformation that this DNA molecule most likely adopts in the free state. The possible relevance of these findings to the process of bis-intercalation and to the pharmacological action of these compounds is discussed.