Researchers have reconstructed molecular communication interfaces that could aid in advancing nanotechnology development. Université de Montréal researchers Dominic Lauzon, PhD, and Alexis Vallée-Bélisle, PhD, have developed a highly programmable DNA-based switch that is triggered by a multivalent assembly. The formation of a multivalent assembly can rationally control the properties of molecular switches, improving their binding efficiency, modifying the drug release properties of DNA cargo, lengthening the residence time of activated switches, or programming DNA-based computation, among many other uses in DNA-based nanotechnologies.

The research, “Programming Chemical Communication: Allostery vs Multivalent Mechanism,” was published in the Journal of the American Chemical Society.

Through billions of years of evolution, cells have developed a myriad of finely regulated nanomachines that monitor variations in their surroundings. Cells rely on molecular switches that exploit different mechanisms to detect and integrate these specific chemical or physical inputs (e.g., temperature, pressure, pH, small molecules, and proteins) into relevant biological activity to respond to these molecular changes.

Two ways that biomolecular switches become more sensitive to the presence of a molecular input (target) are allosteric and multivalent activation. Allosteric activation depends on the presence of an activator molecule that favors a higher affinity conformation of the switch, while multivalent activation works when an activator molecule binds to the molecular switch and adds another binding interface.

Lauzon and Vallée-Bélisle designed, modeled, and tested a basic DNA-based switch that can be activated using both mechanisms to facilitate a rigorous test to comprehend these activating mechanisms and compare their benefits and drawbacks. The research team demonstrates that even more programming flexibility is possible for the multivalent molecular switch’s affinity, dynamic range, and activated half-life than with the use of an allosteric activator and exploits the programmable feature of the multivalent mechanisms to develop a programmable biosensor for antibody detection.

Lauzon and Vallée-Bélisle highlight the possibility of using highly programmable and versatile DNA-DNA interactions to control molecular switches through multivalent activation mechanisms. DNA synthesis and modification with chemical moieties (like fluorophores, quenchers, redox, and photoactive elements) are easier because their interactions are predictable. This makes it possible to build nanostructures that are precise and well-defined.

The authors concluded: “The simplicity by which the activation properties of molecular switches can be rationally tuned using multivalent assembly suggests that it may find many applications in biosensing, drug delivery, synthetic biology, and molecular computation fields, where precise control over the transduction of binding events into a specific output is key.”

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