Supramolecular Recognition of a DNA Four-Way Junction by an M₂L₄ Metallo-Cage, Inspired by a Simulation-Guided Design...

Area of Science:

• Supramolecular Chemistry
• Chemical Biology
• Biophysical Chemistry

Background:

• DNA four-way junctions (4WJs) are crucial in DNA repair, recombination, and viral regulation, presenting attractive therapeutic targets.
• Identifying specific binders for complex DNA structures like 4WJs remains a significant challenge in molecular recognition.
• Existing research on metallo-supramolecular cages primarily focused on internal binding, not external surface interactions.

Purpose of the Study:

• To develop and characterize novel cationic metallo-supramolecular M2L4 cages as binders for DNA four-way junctions (4WJs).
• To investigate the binding affinity and selectivity of these cages towards 4WJs compared to other DNA structures.
• To explore the potential of exploiting the external aromatic surfaces of supramolecular cages for DNA binding applications.

Main Methods:

• Utilized molecular dynamics (MD) simulations to assess the fit between metallo-supramolecular cages and DNA structures.
• Employed biophysical experiments to determine binding affinities and confirm simulation predictions.
• Synthesized and characterized M2L4 cages with square planar Pd or Pt and anthracene-based ligands.

Main Results:

• Cationic metallo-supramolecular M2L4 cages exhibit nanomolar binding affinities for DNA 4WJs.
• The size and shape of the cages, featuring Pd/Pt and anthracene ligands, provide an excellent fit for the 4WJ cavity.
• 4WJs were identified as the preferred DNA target, with preferential binding to T-shape bulged 3WJs over perfect Y-shaped 3WJs, and no binding to duplex B-DNA.
• The study successfully exploited the external aromatic surfaces of the cages for DNA binding, creating a supramolecular guest-DNA host match.

Conclusions:

• Metallo-supramolecular M2L4 cages represent a novel class of high-affinity binders for DNA 4WJs.
• The rational design of supramolecular structures based on shape complementarity can effectively target specific DNA conformations.
• This approach offers a powerful strategy for accelerating the discovery of novel nucleic acid-targeting agents.