Unfolding of i-Motif DNA Structures Using G-Quadruplex Stabilizing Bisindolylmaleimide Ligands

Area of Science:

• Biochemistry
• Molecular Biology
• Chemical Biology

Background:

• i-Motif (iM) DNA structures form from C-rich sequences and are involved in gene regulation.
• G-quadruplex (G4) structures are also key regulatory elements in the genome.
• The formation of iM and G4 structures is typically mutually exclusive.

Purpose of the Study:

• To investigate the interaction of G4 stabilizers with iM structures.
• To explore the potential of small molecules targeting both G4 and iM DNA motifs.
• To understand how ligands affect the stability and conformation of iM structures.

Main Methods:

• Circular Dichroism (CD) spectroscopy
• Nuclear Magnetic Resonance (NMR) titration
• Molecular Dynamics (MD) simulations

Main Results:

• G4 stabilizers BIM-Pr1 and BIM-Pr2 were shown to interact with telomeric and promoter iM structures.
• These ligands induced destabilization and conformational unfolding of iM structures.
• The study demonstrated an unexpected interaction between G4-stabilizing ligands and iM DNA.

Conclusions:

• Ligands designed as G4 stabilizers can also influence iM structures.
• The findings suggest a novel strategy for developing bifunctional ligands targeting both G4 and iM motifs.
• This research has implications for the design of new therapeutic agents and biosensors.