Molecular mechanics calculations on the complexes between analogues of Hoechst 33258 and d(CGCGAAT-TCGCG)2: influence of bulky group substitution on base pair preference of DNA minor groove binders

Molecular mechanics calculations were performed on the three structures of the complexes formed by the derivatives of Hoechst 33258 and dodecameric DNA duplex d(CGCGAATTCGCG)2. Formation and docking energies of these complexes were compared. It was found that the CG site that is 3′ to the central AATT region can be tolerated by the drugs. This is probably due to the presence of the bulky piperazine ring and, more pronouncedly, by alkylated analogues of the drug that prefer the wider minor groove formed by the GC base pair region of B-DNA. The argument of bulkiness of the piperazine moiety as the origin of enhancement of GC affinity is supported by detailed structural analysis of the intermolecular interface and widening of the DNA minor groove at the binding site. Implications of the results are discussed. Keywords: minor groove binder, docking energy, sequence specificity.