Interaction of Ru(II) Complexes and DNA

    reproduced from N. Turro, J. Barton and D. Tomalia, Acc. Chem. Res., 1991, 24, 332-340

Three modes of association between metal complexes and DNA are generally distingished :

External binding         Groove binding         Intercalation

Clicking on one of the complex will bring you to more information about the association mode represented.

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External binding

External association of the complexe in the atmosphere of ions of the DNA polyelectrolyte.

This association is electrostatic in nature (Ru(II) complexes are 2+ positively charged and the DNA phosphate sugar backbone is negatively charged). This association mode was proposed for [Ru(BPY)3]2+ as the luminescence enhancement of this complex upon binding to DNA is strongly dependent on the ionic strenght. Cations as Mg2+ usually interacts also in this way.

J. Kelly, A. Tossi, D. McConnell, Oh Uigin, Nucl. Acids Res., 1985, 13, 6017

Groove binding

Adsorption of the complexe in the DNA grooves.

The molecules approaches within van der Waals contact and resides in the DNA groove. Hydrophobic and/or hydrogen-bonding are usually important components of this binding process, and provide stabilisation. The antibiotic netropsin is a model groove-binder (to see the X-ray structure of this groove-binder click on the molecule). Geometric and steric factors also play a role as shown with [Ru(TMP)3]2+ (TMP = 3,4,7,8-tetramethyl phenanthroline) where the methyl groups prevent intercalation.

H. Mei, J. Barton, J. Am. Chem. Soc., 1986, 108, 7414

Intercalation

Intercalation of a planar ligand of the complex in the DNA base pairs stack.

This association involves the insertion of a planar fused aromatic ring system between the DNA base pairs, leading to significant p-electron overlap. This mode of binding is stabilised by stacking interactions and is thus less sensitive to ionic strenght relative to the two other binding modes. This mode of binding is usually favoured by the presence of an extended fused aromatic ligand as PHEHAT [1] or DPPZ [2]. Indeed with less extended aromatic systems, the intercalation is usually prevented through clashing of the ancillary ligands with the phosphodiester backbone, so that only partial intercalation can occur as it is the case for [Ru(phen)3]2+ [3].

You can find more information concerning the potential application, i.e. the light switch effect, of PHEHAT complexes in another part of the introduction concerning the photoprobes.

A battery of complementary methods is necessary to determine the binding modes of a complex to DNA. These methods can be used to evidence the effect of association of the complex on the properties of DNA or/and on the properties of the complex itself.

Particularly, intercalation can be evidenced by

• Intercalation produces an increase of viscosity of the DNA double helix [2] as insertion of the ligand among the DNA base pairs stack induces a lenghtening of DNA. This method is generally considered as the more convenient to probe intercalation. The increase of DNA lenght has also been probed recently by Atomic Force Microscopy [4].
• Another very efficient tool to probe intercalation is the linear dichroism (schematically shown in the case of [Ru(phen)2DPPZ]2+)[5]. It allows to determine the angle between the absorbing transition dipole moment of the complex and the DNA helix axis oriented by flow or electric field. Nevertheless, this methods implies to work with enantiomerically pure complexes and requires also a precise determination of the orientation of the transition dipole moment.
• Differential quenching of the bound species
  • by positively charged quenchers furnish information about the binding modes also [6].
  • by negatively or neutral quenchers which remains in the bulk solution probe external binding [7].
• 1H-NMR in two dimensions and NOE effects can also be helpfull and allows to probe both partners [8].

[1] C. Moucheron, A. Kirsch-De Mesmaeker, J. Physical Organic Chemistry, 1998, 11, 577-583

[2] I. Haq, P. Lincoln, D. Suh, B. Norden, B. Chowdhry, J. Chaires, J. Am. Chem. Soc., 1995, 117, 4788-4796

[3] P. Lincoln, B. Norden, J. Phys. Chem. B, 1998, 102, 9583-9594

[4] J. Coury, J. Anderson, L. McFail-Isom, L. Williams, L. Bottomley, J. Am. Chem. Soc., 1997, 119, 3792-3796

[5] P. Lincoln, A. Broo and B. Norden, J. Am. Chem. Soc., 1996, 118, 2644-2653

[6] A. Tossi, J. Kelly, Photochemistry and Photobiology, 1989, 49, 545-556

[7] G. Orellana, A. Kirsch-De Mesmaeker, J. Barton and N. Turro, Photochemistry and Photobiology, 1991, 54, 499-509

[8] M. Eriksson, M. Leijon, C. Hiort, B. Norden, A. Gräslund, JBiochemistry, 1994, 33, 5031-5040

Note that for metal complexes, binding modes may be more complicated than for organic molecules, and that neither intercalation, nor groove binding are unambiguous concepts but rather names used to denominate a group of DNA binding modes having important common features.