Ligand binding to G-quadruplex DNA: new insights from ultraviolet resonance Raman spectroscopy

Area of Science:

• Biochemistry
• Molecular Biology
• Spectroscopy

Background:

• G-quadruplexes (G4s) are noncanonical nucleic acid structures crucial for regulating biological processes.
• Designing G4-targeting molecules for anticancer and antiviral therapies is challenging due to G4 structural polymorphism.
• Understanding ligand-G4 interactions is key to developing effective G4-based therapeutics.

Purpose of the Study:

• To demonstrate the utility of Ultraviolet Resonance Raman (UVRR) spectroscopy in studying ligand/G4 interactions in solution.
• To investigate the binding modes of BRACO-19 and Pyridostatin to biologically relevant G4s.
• To elucidate the specific ligand and G4 chemical groups involved in these interactions.

Main Methods:

• Polarized UVRR scattering at 266 nm was employed to study BRACO-19 and Pyridostatin binding to G4s.
• Analysis of spectral peak changes provided insights into molecular interactions.
• Circular dichroism (CD) spectroscopy complemented UVRR data.

Main Results:

• UVRR spectroscopy successfully provided detailed information on ligand-G4 interactions in solution.
• BRACO-19 and Pyridostatin were observed to interact with distinct sites on different G4 structures.
• Specific ligand and G4 chemical groups involved in the binding were identified.
• Ligand binding modes were shown to be dependent on G4 conformation.

Conclusions:

• UVRR spectroscopy is a valuable tool for investigating G4 structures and their interactions with ligands in solution.
• The findings enhance understanding of G4-ligand binding, crucial for therapeutic development.
• This study highlights the importance of considering G4 conformation in drug design.