Structure–Property Relationships in Cu^II‐Binding Tetramolecular G‐Quadruplex DNA

Abstract

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(G₄ )]₄ (L^A-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 L^E 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^E₂ d(G)₄ ]₄ shows that stabilization in the presence of Cu^II is not additive. All results are based on UV/Vis thermal denaturation, thermal difference, circular dichroism experiments and molecular dynamics simulations.