Ligand binding solvation

Fig. 6 Scheme for the binding of a receptor and a ligand in the solvated phase. 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. 

X. Xou, Y. Sun, and I. Kuntz, Inclusion of solvation in ligand binding free energy calculations using the generalized-Bom model, J. Am. Chem. Soc. 121 8033 (1999). 

In order to be able to form stable complexes, a ligand should interact more strongly with the cation than the solvent. The solvation energy has to be overcome by the interaction of the cation with the ligand binding sites. The choice of binding site parameters should thus allow efficient control of the complexation properties of a ligand. 

It is also possible to make some inferences about the nature of the transition state. Fast association rates imply stepwise removal of the solvation shell of the cation by consecutive replacement of each solvent molecule by a ligand binding site, so as to minimize the loss of binding energy in the transition state. The fact that the association rates differ less than the dissociation rates (which follow the stability sequence) could indicate that the transition state is nearer to the reagents than to the complex. Furthermore the slowness of the association could be explained by the operation of the following effects on the way to the transition state ... 

Since binding in solution results from a compromise between interaction with the ligand and solvation, new insights into the origin of the cation recognition process and of the macrocyclic and cryptate effects can be gained from experimental gas phase studies [2.34, 2.35] as well as from computer modelling calculations in vacuo or in a solvent [1.35b, 1.42, 1.43, 1.45, 2.36, 2.37, A.37]. In particular, molecular dynamics calculations indicate that complementarity is reflected in restricted motion of the ion in the cavity [1.45, 2.36]. 

Solvation of cation and ligand. The solvation free energy increases in the order K+ < Na+ < Ca2+, hence less energy is required to (partially) desolvate K+ in order to bind it. 

Solvation in Ligand Binding Free Energy Calculations Using the Generalized-Born Model. 

Conformational Flexibility and Solvation on Receptor-Ligand Binding Free Energies. 

Despite the fact that nonpolar hydration forces dominate whenever hydrophobic interactions [46] are important, the general availability of accurate models for the nonpolar component of the hydration-free energy is lacking. The structure and properties of proteins in water is highly influenced by hydrophobic interactions [47-50]. Hydrophobic interactions also play a key role in the mechanism of ligand binding to proteins [30,51-53], Empirical surface area models [54] for the nonpolar component of the solvation free energy are widely used [28,37,55-62]. Surface area models are useful as a first... 

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).

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