The factors responsible for the binding of Hoechst 33258 with DNA residues have been investigated in this work using the AM1 method. First and foremost, it is found that, although all crystal structure determinations indicate a preference for binding at AT rich sites, the hydrogen bond strength is actually greater for complexes with cytosine and guanine. From this, it has been inferred that other factors such as electrostatic, van der Waals interactions and nonbonded contacts with the walls of the minor groove have a strong role to play in the binding process. The hydrogen bond is found to be stronger for complexation with the thymine O2 than with the adenine N3, in line with experimental observations. Combined QM/MM studies on the drug complexed with the Dickerson-Drew dodecamer reveal that binding induces structural changes in both the ligand as well as DNA. Electron donating substituents at the para position in the phenyl ring of Hoechst 33258 lead to stronger binding with DNA. A correlation with the octanol/water partition coefficients points to the importance of hydrophobic and electrostatic interactions.

Key words: Molecular recognition; Energy analysis; Hoechst 33258; and Drug-DNA interactions.