Binding site for ethidium cation in the major groove of B-form DNA.

Molecular modeling of the system composed of ethidium cation initially intercalated through the major and minor grooves of the B-DNA form of 5'GCATGC3' into the central AT pairs, with the phenyl group oriented either toward or away from the helical axis, led upon energy minimization to intercalation complexes only when the phenyl group was initially oriented away from the helical axis. For the other two cases, energy minimization led to extrusion of the ethidium from the helix to form unanticipated outside-bound complexes stabilized by specific hydrogen bonds. It is suggested that outside-bound major groove complexes involving the GXXXG sequence may play important roles in the reaction mechanism of ethidium intercalation and in its action as a drug.