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Volume 271, Number 44, Issue of November 1, 1996 pp. 27608-27614
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Simultaneous and Different Binding Mechanisms of 4,6-Diamidino-2-phenylindole to DNA Hexamer (d(CGATCG))₂
A ¹H NMR STUDY

(Received for publication, June 19, 1996, and in revised form, August 13, 1996)

Edoardo Trotta ^§ , Ettore D'Ambrosio , Giampietro Ravagnan and Maurizio Paci

From the  Consiglio Nazionale Ricerche, Istituto di Medicina Sperimentale, Viale Marx 15, I-00137 Rome and the ^§ Dipartimento di Scienze e Tecnologie Chimiche, Universita' di Roma ``Tor Vergata,'' I-00133 Rome, Italy

The solution structure of the complex between 4,6-diamidino-2-phenylindole (DAPI) and DNA oligomer (d(CGATCG))₂ at a 2:1 drug/duplex ratio has been characterized by combined use of proton one- and two-dimensional NMR spectroscopy, molecular mechanics, and molecular dynamics computations. Intermolecular nuclear Overhauser effects (NOEs), DNA structure perturbations, and resonance shifts induced by binding provide evidence that DAPI interacts with DNA hexamer by two different binding mechanisms, in fast exchange on the NMR time scale, without any significant distortion of the B-type conformation of DNA hexamer. The results indicate that the ligand binds into the minor groove of the central 5-ATC-3 region of the hexamer and on the outside of the oligomer by a ,-stacking interaction with the terminal C1:G6 base pairs. A model for both binding mechanisms that accounts for all experimental data was generated by molecular mechanics and dynamics calculations based on experimental NOEs. In the minor groove binding, N2 amino group of G2 precludes a deep insertion of phenyl ring of DAPI into the groove. Position and orientation of the drug in the external stacking interaction resemble those suggested for intercalation of DAPI between C:G base pairs.

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