Entropic ligand binding

As shown in Figure 6, the solvent molecules tend to be ordered around the molecules and when the protein and the ligand bind, several of these molecules are liberated and become disordered (entropic effect). Therefore, upon complex formation water molecules are released, receptor and ligand lose degrees of freedom and the interaction between the ligand and the receptor is calculated. 

Figure 3 Overview of the receptor-ligand binding process. All species involved are solvated by water (symbolized by gray spheres). The binding free energy difference between the bound and unbound state is a sum of enthalpic components (breaking and formation of hydrogen bonds, formation of specific hydrophobic contacts), and entropic components (release of water from hydrophobic surfaces to solvent, loss of conformational mobility of receptor and ligand).

Outliers in QSAR 1.92 included the 4-t-butyl and 4-OH analogs, whereas the 4-CONH, analog was an outlier in QSAR 1.93. These results were recently reanalyzed by Kim (217,218) with respect to the role of enthal-pic and entropic contributions to ligand binding with a-chymotrypsin. Use of the Fu-jiwara hydrophobic enthalpy parameter n and the hydrophobic entropy parameter irg led to the development of QSAR 1.94 and 1.95(219). 

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