Programing Chemical Communication: Allostery vs Multivalent Mechanism

The emergence of life has relied on chemical communicationandthe ability to integrate multiple chemical inputs into a specificoutput. Two mechanisms are typically employed by nature to do so:allostery and multivalent activation. Although a better understandingof allostery has recently provided a variety of strategies to optimizethe 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 designprinciples of both mechanisms, we have engineered a highly programmableDNA-based switch that can be triggered by either a multivalent oran allosteric DNA activator. By precisely designing the binding interfaceof the multivalent activator, we show that the affinity, dynamic range,and activated half-life of the molecular switch can be programed witheven more versatility than when using an allosteric activator. Thesimplicity by which the activation properties of molecular switchescan be rationally tuned using multivalent assembly suggests that itmay find many applications in biosensing, drug delivery, syntheticbiology, and molecular computation fields, where precise control overthe transduction of binding events into a specific output is key.