Programing Chemical Communication: Allostery vs Multivalent Mechanism

The emergence of life has relied on chemical communication and the ability to integrate multiple chemical inputs into a specific output. Two mechanisms are typically employed by nature to do so: allostery and multivalent activation. Although a better understanding of allostery has recently provided a variety of strategies to optimize the binding affinity, sensitivity, and specificity of molecular switches, mechanisms relying on multivalent activation remain poorly understood. As a proof of concept to compare the thermodynamic basis and design principles of both mechanisms, we have engineered a highly programmable DNA-based switch that can be triggered by either a multivalent or an allosteric DNA activator. By precisely designing the binding interface of the multivalent activator, we show that the affinity, dynamic range, and activated half-life of the molecular switch can be programed with even more versatility than when using an allosteric activator. 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.