Specificity in the interaction of non intercalative groove binding ligands with nucleic acids

This paper presents results of theoretical computations on the interaction energies and geometries for the binding to nucleic acids of a number of representative groove binding non intercalating drugs: netropsin, distamycin A, SN 18071, etc. The computations account for the specificity of binding in all cases and demonstrate that the formation of hydrogen bonds is not necessary neither for binding nor for the preference for the minor groove of AT sequences of B-DNA. It appears that if a relatively good steric fit can be obtained in the minor groove, the interaction will be preferentially stabilized there by the favorable electrostatic potential generated in this groove by the AT sequences. The computation of the interaction energies in free space does not reproduce, however, the order of affinities of the ligands studied and yields too great values of the binding energies. The introduction of the solvent effect, through the computation of the hydration and cavitation effects, confirms the specificity, improves the ordering and brings the values of the energies close to the experimental ones. The theoretical account of the “surprising” effect of netrospin binding to the major groove of theTψC stem of tRNA^Phe confirms the decisive significance of the distribution of the molecular electrostatic potential for the selection of the binding site. The inclusion in the computations of the flexibility of DNA enables to predict correctly the main features of the macromolecular deformation upon the binding of the ligand.