Binding Modes and Selectivity of Ruthenium Complexes to Human Telomeric DNA G‐Quadruplexes

Abstract

Metal complexes constitute an important class of DNA binders. In particular, a few ruthenium polyazaaromatic complexes are attractive as “light switches” because of their strong luminescence enhancement upon DNA binding. In this paper, a comprehensive study on the binding modes of several mononuclear and binuclear ruthenium complexes to human telomeric sequences, made of repeats of the d(TTAGGG) fragment is reported. These DNA sequences form G‐quadruplexes (G4s) at the ends of chromosomes and constitute a relevant biomolecular target in cancer research. By combining spectroscopy experiments and molecular modelling simulations, several key properties are deciphered: the binding modes, the stabilization of G4 upon binding, and the selectivity of these complexes towards G4 versus double‐stranded DNA. These results are rationalized by assessing the possible deformation of G4 and the binding free energies of several binding modes via modelling approaches. Altogether, this comparative study provides fundamental insights into the molecular recognition properties and selectivity of Ru complexes towards this important class of DNA G4s.

Structural Studies Reveal Enantiospecific Recognition of a DNA G‐Quadruplex by a Ruthenium Polypyridyl Complex

“…In the L,L enantiomer model, there are stacking interactions between an ancillary bpy ligand and athymine residue in the loop,and it is estimated to bind about 40 times more strongly ( Figure S10). Form ononuclear complexes,t here are modelling studies [24] rather than NMR or crystal structure evidence. There are only four other published crystal structures showing .…”

“…Thev ulnerability of the 5'-guanosine of aG -quadruplex to chemical damage has been established in ad etailed study by Burrows et al [22] Only two NMR structures of binuclear ruthenium complexes bound to G-quadruplexes have previously been reported, [23] with the L,L enantiomer of the binuclear ruthenium complex threaded through ad iagonal loop of an antiparallel quadruplex, but the D,D enantiomer end-stacked to the lateral loop end of the same conformation. Form ononuclear complexes,t here are modelling studies [24] rather than NMR or crystal structure evidence. Form ononuclear complexes,t here are modelling studies [24] rather than NMR or crystal structure evidence.…”

Induction of C-Myc G-Quadruplex Dna and Cytotoxicity of a Calix[]arene-Containing Binuclear Ruthenium(ii) Complex

“…As illustrated in Fig. 2, excitation of the complex at 460 nm in Tris-KCl buffer resulted in an intense 3 MLCT {Ru(dπ)→ligand(π*)} emission band with λmax around 610 nm. As increasing the concentration of c-myc Pu27 or Pu22 DNA, the situation of emission for the complex is interesting.…”

Structural Studies Reveal Enantiospecific Recognition of a DNA G‐Quadruplex by a Ruthenium Polypyridyl Complex

“…In the Λ,Λ enantiomer model, there are stacking interactions between an ancillary bpy ligand and a thymine residue in the loop, and it is estimated to bind about 40 times more strongly (Figure S10). For mononuclear complexes, there are modelling studies rather than NMR or crystal structure evidence. There are only four other published crystal structures showing metal complex binding to quadruplexes (with structurally unrelated planar species)—two salphen complexes, and two gold complexes—with all these giving parallel‐stranded assemblies in the crystal, in contrast to the antiparallel arrangement reported here.…”