Switching on Supramolecular DNA Junction Binding Using a Human Enzyme.

Area of Science:

• Supramolecular Chemistry
• Chemical Biology
• Biotechnology

Background:

• Non-canonical DNA structures are crucial in human diseases and nucleic acid nanoscience.
• Controlling the binding and modulation of these DNA structures is an area of active research.
• Developing targeted binding agents for specific DNA structures is a key challenge.

Purpose of the Study:

• To design a metallo-supramolecular agent capable of binding non-canonical DNA junctions.
• To achieve enzyme-activated, "on-command" control over DNA junction binding.
• To establish a system with NAND logic control based on enzyme presence and cofactor availability.

Main Methods:

• Development of a metallo-supramolecular triple-helicate cylinder with enzyme-cleavable arms.
• Utilizing NAD(P)H:quinone oxidoreductase 1 (NQO1) and nicotinamide adenine dinucleotide phosphate (NADPH) for activation.
• Employing computational modeling to understand binding activation mechanisms.

Main Results:

• An inert metallo-supramolecular cylinder was engineered, which becomes active upon enzymatic reduction.
• Enzyme-mediated removal of six terminal quinone-bearing arms transforms the cylinder into a DNA junction-binding agent.
• The system demonstrated NAND logic control, activating binding in response to NQO1, NADPH, and the absence of an inhibitor.
• Computational analysis suggested conformational flexibility changes, rather than steric unblocking, drive binding activation.

Conclusions:

• A novel enzyme-activated supramolecular system for controlling DNA junction binding has been developed.
• This system offers precise "on-command" control, responding to specific biological stimuli.
• The findings provide a foundation for designing sophisticated, inert supramolecular structures that can be activated by enzymes for diverse applications.