The molecular structure of the complex of Hoechst 33258 and the DNA dodecamer d(CGCGAATTCGCG)

Abstract

The crystal structure of the complex between the dodecamer d(CGCGAATTCGCG) and a synthetic dye molecule Hoechst 33258 was solved by X-ray diffraction analysis and refined to an R-factor of 15.7% at 2.25 A resolution. The crescent-shaped Hoechst compound is found to bind to the central four AATT base pairs in the narrow minor groove of the B-DNA double helix. The piperazine ring of the drug has its flat face almost parallel to the aromatic bisbenzimidazole ring and lies sideways in the minor groove. No evidence of disordered structure of the drug is seen in the complex. The binding of Hoechst to DNA is stabilized by a combination of hydrogen bonding, van der Waals interaction and electrostatic interactions. The binding preference for AT base pairs by the drug is the result of the close contact between the Hoechst molecule and the C2 hydrogen atoms of adenine. The nature of these contacts precludes the binding of the drug to G-C base pairs due to the presence of N2 amino groups of guanines. The present crystal structural information agrees well with the data obtained from chemical footprinting experiments.

Intrinsic Conformational Preferences of the Hoechst Dye Family and their Influence on DNA Binding

“…This drug is known to bind strongly to double-stranded B-DNA (Harshman and Dervan, 1985) with specificity for AT-rich sequences (Latt and Wohlleb, 1975;Murray and Martin, 1988;Embrey et al, 1993). The interaction of Hoechst 33258 with DNA has been extensively studied using X-ray crystallography (Pjura et al, 1987;Teng et al, 1988;Carrondo et al, 1989;Quintana et al, 1991 ;Spink et al, 1994;Vega et al, 1994) and NMR spectroscopy (Fede et al, 1991(Fede et al, , 1993Parkinson et al, 1989Parkinson et al, , 1990Parkinson et al, , 1992. Solution and crystal structures show important differences in some cases (Fede et al, 1993), but together the results provide important information about the binding of Hoechst 33258 to DNA at the atomic level.…”

Crystal Structure of γ‐Oxapentamidine Complexed with d(CGCGAATTCGCG)2

“…As a result, many crystal structures have been determined with a range of DNA minorgroove-binding ligands complexed with this DNA molecule (e.g. Teng et al, 1988;Brown et al, 1990).…”

Interaction of Two Flavonoids With Calf Thymus Dna: A Multi - Spectroscopic, Electrochemical and Molecular Modelling Approach

“…In this paper DNA interaction of two compounds with DNA is reported. [24][25] The interaction is carried out with Calf Thymus DNA and studied via spectroscopic and cyclic voltammetric analysis. 26 Furthermore, molecular modeling methods can be applied to study of interaction drugs and biomacromolecules for saving time and money, especially since the reactivity of newly designed drugs with their targeted biomolecules can be predicted prior to chemical synthesis.…”