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Dissecting the Dynamic Pathways of Stereoselective DNA Threading Intercalation
Ali A Almaqwashi1, Johanna Andersson2, Per Lincoln3
1Department of Physics, Northeastern University, Boston, Massachusetts.
Biophysical Journal
|March 31, 2016
Summary
Chiral DNA threading intercalators show significant stereoselectivity in binding affinity. This study reveals how the chirality of ruthenium complexes influences DNA intercalation, crucial for developing targeted therapeutics.
Area of Science:
- Biochemistry
- Molecular Biology
- Chemical Biology
Background:
- DNA intercalators are key in developing targeted therapeutics.
- Understanding stereoselectivity in DNA-ligand interactions is crucial.
- Dumbbell-shaped DNA threading intercalators offer complex structural insights.
Purpose of the Study:
- Investigate DNA threading intercalation using binuclear ruthenium complexes (Piz).
- Determine the impact of stereoisomerism on DNA binding affinity and kinetics.
- Elucidate the role of chirality in DNA-ligand interactions.
Main Methods:
- Utilized optical tweezers for single DNA molecule elongation measurements.
- Employed force spectroscopy to analyze DNA intercalation dynamics.
- Quantified binding affinity (Kd), equilibrium elongation (Δxeq), and kinetic parameters (xon, xoff).
Main Results:
- Piz stereoisomers exhibited over 20-fold differences in DNA binding affinity.
- Binding affinity correlated with Δxeq and xon, with limited xoff changes.
- Right-handed intercalating subunits enhanced affinity 10-fold; left-handed distal subunits enhanced it 2- to 5-fold.
Conclusions:
- Demonstrated significant stereoselectivity in DNA threading intercalation by Piz complexes.
- Highlighted the critical role of chiral recognition in optimizing DNA binding affinity and kinetics.
- Findings provide a foundation for designing stereochemically controlled DNA-targeted therapeutics.
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