Recent calorimetric studies of interactions between small molecules and biomolecular
targets have generated renewed interest in the phenomenon of entropy-enthalpy
compensation. In these studies, entropic and enthalpic contributions to binding are observed
to vary substantially and in an opposing manner as the ligand or protein is modified,
whereas the binding free energy varies little. In severe examples, engineered enthalpic
gains can lead to completely compensating entropic penalties, frustrating ligand design …