Copper-modified G-Quadruplex DNA as EPR Probes for Precise Distance Measurements

• Applicants: Professor Dr. Guido Clever; Professorin Dr. Müge Kasanmascheff
• Subject Area: Inorganic Molecular Chemistry - Synthesis and Characterisation
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 499176469

DNA G-quadruplexes show a pronounced tendency to form higher-order structures, such as π-stacked dimers, beads-on-a-string wires, and aggregates with aromatic binding partners, relevant in medicinal targeting of telomers and oncogenes. Reliable methods for determining the structure of these non-covalent adducts are scarce. We developed G-quadruplex-based spin-labels containing square-planar Cu(pyridine)4 complexes, covalently incorporated into oligonucleotides, for detecting dimeric structures and measuring intermolecular distances via pulsed dipolar EPR spectroscopy. Furthermore, intercalation of flat molecules into G-quadruplex dimers, resulting in sandwich complexes can be investigated, and previously unknown binding modes discovered. This project applies the transition metal labeling approach, combined with pulsed EPR spectroscopy, to systematically examine an advanced set of structures of non-covalent DNA aggregates, including metal-complexes, supramolecules and DNA-binding proteins. Furthermore, G-quadruplex-based spin labels will be employed to measure distances in other DNA secondary- and tertiary structures such as double strands, bent duplex adducts and G-quadruplex wires. The combination with organic spin labels and ENDOR-active 19F substituents further enhances the applicability of this approach.

• DFG Programme: Research Grants