Energetic and entropic factors determining binding affinity in protein-ligand complexes.

Understanding of non-covalent interactions in protein-ligand complexes is essential in modern biochemistry and should contribute toward the discovery of new drugs. The affinity of a ligand toward its receptor falls into a range of 10-80 kJ/mol. It is related to the binding constant and corresponds to a free energy. Accordingly enthalpic and entropic effects determine binding affinity. Hydrogen bonds and lipophilic contacts are the most important contributions to protein-ligand interactions. They are governed by changes in entropy and enthalpy. Solvation and desolvation effects either of the ligand and the protein binding site play a key role in the binding process. Prerequisite for a quantitative description and subsequently for a prediction of protein-ligand interactions is a partitioning in additive group contributions. In many cases, this additivity seems to be a good approximation, however, phenomena such as conformational pre-organizations give rise for a non-additive behavior. Flexibility and mobility of the bound ligand influence binding affinity. The rare experiments separating enthalpic and entropic contributions to the binding affinity sometimes reveal surprisings results, e.g. the loss of a hydrogen bond parallels with a loss in entropy.