Calorimetric studies of protein-small molecule interactions decompose the standard free energy of binding into the binding enthalpy and entropy-the so-called thermodynamic signature of binding . These components of the free energy may provide insight into the forces driving binding . It has also been argued that one should aim to design ligands whose binding is enthalpydriven, as these may be better drugs than ones whose binding is entropy-driven . On the other hand, small changes in the chemical structure of a ligand often produce large changes in the binding enthalpy and entropy that are difficult to rationalize . Of particular interest here, several meticulous experimental studies have compared the binding of flexible versus preorganized ligands to small proteins. A better preorganized ligand is expected to binding with higher affinity, all other things being equal, due to a reduced configurational entropy penalty on binding, but calorimetric studies have yielded the opposite result . A molecular level understanding of the relationships between ligand structure and binding thermodynamics is of fundamental interest, and may ultimately help to guide design of promising drug candidates.