Collision-induced transfer enhances ligand-binding kinetics in guanine quadruplex DNA

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Guanine quadruplexes (G4s) are non-canonical DNA structures with significant roles in cellular regulation.
• G4s are implicated in oncogenesis, making them key targets for cancer therapeutics.
• Understanding G4/ligand interactions is crucial for developing effective G4-targeting drugs.

Purpose of the Study:

• To introduce and utilize relaxation dispersion nuclear magnetic resonance (RD-NMR) for characterizing G4/ligand interactions.
• To investigate the binding mechanism of the ligand TMPyP4 with a G4 from the cMYC promoter.
• To explore novel mechanisms of ligand transfer involving G4 structures.

Main Methods:

• Relaxation dispersion nuclear magnetic resonance (RD-NMR) to study G4/ligand dynamics.
• Investigated ligand binding and dissociation kinetics.
• Confirmed findings using surface plasmon resonance (SPR).

Main Results:

• Observed slow ligand dissociation from G4s at low concentrations.
• Discovered that ligand dissociation increased with free G4 concentration, indicating collision-induced transfer.
• Demonstrated similar collision-induced ligand transfer between G4s and double-stranded DNA.

Conclusions:

• Reported the first observation of collision-induced ligand transfer involving guanine quadruplexes.
• This mechanism may help therapeutic ligands escape kinetic traps, potentially improving drug efficacy.
• Collision-induced transfer could be a significant factor in G4-based therapeutic strategies.