Entropic effects, ligand-protein interaction

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. 

The family of methods that make direct use of experimentally determined protein structures has their fundamental basis in direct physical simulation. Figure 2.4 cartoons the process of protein and ligand in a solvated and unbound state (left) moving into a bound state (right). While the cartoon may appear simple, the specific physical interactions each have multiple enthalpic and entropic effects, some of which are indirect The association of a hydrophobic Ugand surface with a complementary hydrophobic protein surface involves a direct enthalpic effect from the Van der Waals interactions. But the indirect effects include those from solvent molecules that had occupied the protein site in a semiordered state, which are released as a consequence of ligand occupancy near the protein. These solvent molecules may achieve greater entropy when free within solvent, and they may make more enthalpically favorable... 

Work from Sturtevant s laboratory detailed the kinetics and thermodynamics of zinc binding to apocarbonic anhydrase (carbonate dehydratase) selected data are recorded in Table II (Henkens and Sturtevant, 1968 Henkens etal., 1969). The thermodynamic entropy term A5 at pH 7.0 is 88 e.u. (1 e.u. = 1 cal/mol-K), and this is essentially matched by the binding of zinc to the hexadentate ligand cyclohexylenediamine tetraacetate where AS = 82 e.u. At pH 7.0 the enthalpy of zinc-protein association is 9.8 kcal/mol, but this unfavorable term is overwhelmed by the favorable entropic contribution to the free energy (AG = AH - T AS), where —TAS = -26.2 kcal/mol at 298 K (25°C). Hence, the kinetics and thermodynamics of protein-zinc interaction in this example are dominated by very favorable entropy effects. 

Finally, so-called hydrophobic or lipophilic interactions are often mentioned as additional contribution to protein-ligand interactions. These term s are used to describe the preferential association of nonpolar groups in aqueous solution. It should be emphasized, however, that in contrast to what the name suggests, there is no special hydrophobic force. Instead, one should speak of a hydrophobic effect. As further mentioned below, according to the generally accepted view, it arises primarily from the entropically favorable replacement and release of water molecules (42, 43). The association between the nonpolar surfaces itself is simply based on weak London forces... 

Surface waters are displaced on formation of the protein-ligand complex and thus provide a favorable entropic contribution to the free energy of complex formation. In particular, displacement of the water found interacting on apolar surfaces makes a large contribution to the AG and provides the driving force for many interactions (the hydrophobic effect). 

---