Physicochemical Basis of Protein-Ligand Recognition

At the simplest level, the association between two binding partners is both entropically disfavored due to the loss of translational and rotational degrees of freedom and enthalpically favored due to the interactions formed upon association. However, there is much more involved in protein-ligand complex formation, mostly because the interaction partners are flexible systems and the association occurs in aqueous solution. 

Water plays further important roles with respect to enthalpy and entropy. Interactions between hydrophobic partners are favorable in water as the association reduces the net hydrophobic surface in contact with the polar solvent, thus reducing structured and constrained water around the solutes and providing positive association entropy. Hence, this release of ordered water molecules is an entropy-driven 

Important interactions also occur between nonpolar parts of molecules, preferably at short distances. These are due to dispersion or London forces, which are weakly attractive intermolecular forces. A tight surface fit between nonpolar ligand and binding site areas leads to significant intermolecular forces through the summation of many individual short-range contributions. 

Weakly polar interactions in proteins and protein-ligand complexes are frequently phenomenologically analyzed and classified in terms of the interacting partners [29]. This especially includes interactions with Jt-systems, such as the NH-jt, OH-jt, or CH-Jt interaction [30, 31], aromatic-aromatic interactions (parallel jt-jt stacking versus edge-to-face interaction), and the cation-jt interaction [32]. All of these can 

Val213 d2 Centroid - CanIroKE (6.628 A) Anjla Plane Ringl-Ring2 (100.3=) 

---