Gathering precise knowledge on weak supramolecular interactions is difficult yet is of utmost importance for numerous scientific fields, including catalysis, crystal engineering, ligand binding, and protein folding. We report on a combined theoretical and experimental approach showing that it is possible to vastly improve the sensitivity of current methods to probe weak supramolecular interactions in solution. The concept consists of using a supramolecular platform involving a highly cooperative configurational transition, the perturbation of which (by the modification of the molecular building blocks) can be monitored in a temperature scanning experiment. We tested this concept with a particular bisurea platform, and our first results show that it is possible to detect the presence of interaction differences as low as 60 J/mol, which may be due to steric repulsion between vinyl and alkyl groups or may be the result of solvation effects.