DNA Mimic Foldamer Recognition of a Chromosomal Protein

Area of Science:

• Chemical Biology
• Biophysical Chemistry
• Structural Biology

Background:

• DNA-protein interactions are fundamental to cellular processes.
• Chromosomal protein Sac7d binds DNA non-sequence-selectively, inducing DNA kinking.
• Developing synthetic molecules to mimic or modulate DNA-protein interactions is of significant interest.

Purpose of the Study:

• To synthesize and characterize helical aromatic oligoamide foldamers as DNA mimics.
• To investigate the binding interactions between these foldameric DNA mimics and the Sac7d protein.
• To elucidate the structural basis of foldamer-Sac7d interaction and compare it to DNA-Sac7d binding.

Main Methods:

• Synthesis of anionic helical aromatic oligoamide foldamers.
• Biophysical techniques including Surface Plasmon Resonance (SPR), Isothermal Titration Calorimetry (ITC), and Circular Dichroism (CD) spectroscopy.
• Structural analyses using Atomic Force Microscopy (AFM), Nuclear Magnetic Resonance (NMR), and single crystal X-ray crystallography.

Main Results:

• Foldamers successfully mimic the shape and charge distribution of DNA.
• Foldamers exhibit stronger binding affinity to Sac7d compared to a DNA duplex of similar length.
• The interaction is diastereoselective and occurs at the protein's DNA binding site.
• X-ray crystallography reveals a unique binding mode of foldamers to Sac7d, without kinking.

Conclusions:

• Helical aromatic oligoamide foldamers represent a novel class of synthetic DNA mimics.
• These foldamers can effectively bind to DNA-binding proteins like Sac7d, offering an alternative to DNA.
• The distinct binding mode highlights the potential of foldamers to modulate protein-DNA interactions in new ways.