Selective binding of Zn2+ complexes to human telomeric G-quadruplex DNA

Area of Science:

• Biochemistry
• Molecular Biology
• Chemical Biology

Background:

• G-quadruplex DNA structures are crucial in biological processes.
• Selective binding agents for G-quadruplexes are valuable research tools.
• Understanding DNA-metal complex interactions is key to developing new therapeutics and sensors.

Purpose of the Study:

• To investigate the selective binding of the Zn(2+) complex of 5-(1,4,7,10-tetraazacyclododecan-1-ylsulfonyl)-N,N-dimethylnaphthalen-1-amine (Zn(DSC)) to human telomeric G-quadruplex (H-Telo).
• To characterize the binding mechanism, stoichiometry, and pH dependence of the Zn(DSC)-H-Telo interaction.
• To explore the potential of the Zn(DSC)-H-Telo adduct as a zinc ion sensor.

Main Methods:

• Fluorescence spectroscopy to monitor binding.
• Isothermal titration calorimetry (ITC) to determine binding constants and stoichiometry.
• pH-dependent studies to understand interaction mechanisms.
• Nuclear Magnetic Resonance (NMR) spectroscopy to elucidate binding sites on oligonucleotides.

Main Results:

• Zn(DSC) selectively binds to H-Telo G-quadruplex over duplex DNA.
• Binding is pH-dependent, suggesting interaction with thymine bases in G-quadruplex loops.
• ITC confirmed low micromolar dissociation constants and a 2:1 stoichiometry for the H-Telo-Zn(DSC) adduct.
• The H-Telo-Zn(DSC) complex self-assembles at physiological conditions, indicating potential for Zn(2+) sensing.
• Zn(DSC) forms 2:1 adducts with spaced thymines but not tandem thymines, consistent with binding to separate G-quadruplex loops.

Conclusions:

• Zn(DSC) is a selective binder of the H-Telo G-quadruplex, with binding influenced by pH and thymine base accessibility.
• The self-assembly property of the H-Telo-Zn(DSC) adduct at physiological conditions makes it a promising candidate for a Zn(2+) sensor.
• The findings provide insights into the specific interactions between metal complexes and G-quadruplex structures.