Structure-Property Relationships in Cu-II-Binding Tetramolecular G-Quadruplex DNA

A series of artificial metal-base tetrads composed of a Cu-II cation coordinating to four pyridines, covalently attached to the ends of tetramolecular G-quadruplex DNA strands [L(A-D)d(G(4))](4) (LA-D = ligand derivatives), was systematically studied. Structurally, the square-planar [Cu(pyridine)(4)] complex behaves analogously to the canonical guanine quartet. Copper coordination to all studied ligand derivatives was found to increase G-quadruplex thermodynamic stability, tolerating a great variety of ligand linker lengths (1-5 atoms) and thus demonstrating the robustness of the chosen ligand design. Only at long linker lengths, the stabilizing effect of copper binding is compensated by the loss of conformational freedom. A previously reported ligand LE with chiral backbone enables incorporation at any oligonucleotide position. We show that ligand chirality distinctly steers Cu-II-induced G-quadruplex stabilization. 5'-End formation of two metal-base tetrads by tetramolecular G-quadruplex [L(2)(E)d(G)(4)](4) shows that stabilization in the presence of CuII is not additive. All results are based on UV/Vis thermal denaturation, thermal difference, circular dichroism experiments and molecular dynamics simulations.