Rational Design of Memory‐Based Sensors: the Case of Molecular Calorimeters

Thermodynamic characterization is crucial for understanding molecular interactions. However, methodologies for measuring heat changes in small open systems are extremely limited. We document a new approach for designing molecular sensors, that function as calorimeters: sensors based on memory. To design a memory‐based sensor, we take advantage of the unique kinetic properties of nucleic acid scaffolds. Particularly, we elaborate on the differences in folding and unfolding rates in nucleic acid quadruplexes. DNA‐based i‐motifs unfold fast in response to small heats but do not fold back when the system is equilibrated with surroundings. We translated this behavior into a molecular memory function that enables the measurement of heat changes in open environments. The new sensors are biocompatible, operate homogeneously, and measure small heats released over long time periods. As a proof‐of‐concept, we demonstrate how the molecular calorimeters report heat changes generated in water/propanol mixing and in ligand/protein binding. Currently, no calorimeters that are biocompatible and operate homogeneously are available. Herein, a new approach for the design of molecular calorimeters, an approach based on deliberate control over folding/unfolding rates in nucleic acid scaffolds is reported. The biocompatible calorimeters that operate homogeneously will reveal a new layer of information on molecular interactions in small open systems.