Intrinsic conformational preferences of the Hoechst dye family and their influence on DNA binding

Quantum mechanical calculations have been used to investigate the molecular conformation of the Hoechst family of DNA-binding dyestuffs. Compounds in which the phenolic substituent adopts either a meta or para position were studied. Two different environments have been considered, which are the pas phase and aqueous solution, the conformation in aqueous solution has been modeled through a self-consistent reaction field strategy. The results clearly indicate that Hoechst dyes do not adopt a planar conformation and that the degree of planarity is controlled by the external environment. A comparison with experimental data reveals that the conformation of Hoechst dyes in the gas phase is similar to that observed in DNA complexes by X-ray crystallography. In aqueous solution, the conformation deviates from planarity more than in the gas phase, since non-bonded interactions with the solvent offset the loss of conjugative interactions. The role of the drug conformation in the binding mechanism with DNA is discussed.