Interfacing B-DNA and DNA Mimic Foldamers.

Area of Science:

• Biochemistry
• Synthetic Chemistry
• Molecular Biology

Background:

• Designing artificial nucleic acid structures is crucial for understanding biological processes and developing new therapeutics.
• Creating hybrid molecules combining natural DNA with synthetic foldamers presents challenges in maintaining structural integrity and function.

Purpose of the Study:

• To design and synthesize a linker unit capable of forming a hairpin turn in DNA and anchoring a B-DNA-mimicking foldamer.
• To develop methods for creating chimeric molecules integrating foldamer and DNA segments.
• To demonstrate the precise positioning of foldamer and DNA helices within chimeric structures and confirm their biological activity.

Main Methods:

• Chemical synthesis of a novel linker unit and chimeric DNA-foldamer molecules.
• Structural analysis using single crystal X-ray diffraction and circular dichroism.
• Computational modeling to assess helix positioning and groove/rim registration.
• Bio-layer interferometry to evaluate DNA-binding protein interactions.

Main Results:

• Successful design and synthesis of a linker enabling simultaneous hairpin formation in DNA and foldamer anchoring.
• Demonstration of successful integration of foldamer and DNA segments into chimeric molecules.
• X-ray crystallography and circular dichroism confirmed precise alignment of foldamer and DNA helices, maintaining groove and rim registration.
• Chimeric hairpin DNA duplexes retained their ability to bind DNA-binding proteins.

Conclusions:

• A versatile linker has been developed for constructing chimeric foldamer-DNA molecules with defined structures.
• These artificial molecules maintain key B-DNA characteristics and biological functions, such as protein recognition.
• The developed chimeric molecules represent a promising platform for creating competitive inhibitors of protein-DNA interactions.