Mirror-Image Dependence: Targeting Enantiomeric G-Quadruplex DNA Using Triplex Metallohelices

Area of Science:

• Supramolecular Chemistry
• Biochemistry
• Molecular Biology

Background:

• Natural DNA (d-DNA) and its mirror image (l-DNA) are enantiomers.
• Understanding enantiomeric compound recognition of d-DNA and l-DNA is challenging due to DNA's flexibility and conformational diversity.
• G-quadruplex (G4) DNA exhibits diverse conformations and significant biological functions.

Purpose of the Study:

• To investigate the binding of iron triplex metallohelices to both d- and l-G4 DNA.
• To evaluate the enantioselectivity and binding characteristics of these metallohelices.
• To elucidate the binding mechanism and thermodynamic driving forces.

Main Methods:

• Synthesis and characterization of ten pairs of iron triplex metallohelices.
• Evaluation of binding affinities and stabilization effects using various biophysical techniques.
• Thermodynamic analysis of the binding process.

Main Results:

• The Δ-enantiomer of the metallohelix selectively binds to d-G4 DNA, and the Λ-enantiomer selectively binds to l-G4 DNA.
• Both enantiomers exhibit similar stabilization effects and binding affinities towards their respective DNA enantiomers.
• The Δ-metallohelix demonstrates a significantly higher binding affinity (nearly 70-fold) for d-G4 compared to the Λ-metallohelix binding d-G4.
• Binding of Δ-metallohelix to d-G4 follows a two-step process, primarily driven by favorable enthalpy changes.

Conclusions:

• Iron triplex metallohelices exhibit high enantioselectivity in binding to d- and l-G4 DNA.
• The study provides insights into the molecular recognition mechanisms between chiral metallohelices and enantiomeric DNA structures.
• These findings contribute to the development of novel DNA-targeting agents and understanding of chiral interactions in biological systems.