![]() However, the amount of water hydrating the system can also change and if any of this water is tightly bound, its contribution to the enthalpy and entropy of binding will also be largely compensatory, as pointed out long ago (Lumry and Rajender 1970). ![]() In fact, enthalpy-entropy compensation (EEC) is a widely observed phenomenon and is typically explained by assuming that if a molecular change in the ligand leads to more and/or tighter van der Waals contacts and H-bonds with the substrate (giving a more negative ∆ H), this inevitably leads to reduced mobility/flexibility in either or both components of the interaction, i.e., a reduction in the overall conformational entropy, and that change compensates the enthalpy decrease. If ∆ G remains the same, it follows that changes in ∆ H and T∆ S compensate one another. It is frequently observed that whereas the Gibbs energy of binding, i.e., the binding constant, remains largely unchanged in consequence of the addition/subtraction of chemical groups, there are substantial variations in the component enthalpies and entropies. Faced with such large, and compensating, changes in the enthalpies and entropies of binding, the best approach to engineering elevated affinities must be through the addition of ionic links, as they generate increased entropy without affecting the enthalpy.Įfforts to establish structure–activity relationships (SARs) and improve the affinity of drugs for target proteins typically involve thermodynamic measurements on a panel of modified forms of the lead compound, principally using isothermal titration calorimetry (ITC). Only by assuming substantial changes in solvation-an intrinsically compensatory process-can a more complete understanding of EEC be obtained. However, a substantial contribution from solvation gives the same effect, as a consequence of a structural link between the amount of bound water and the protein flexibility. Two systems exhibiting EEC show a correlation between calorimetric entropies and local mobilities, interpreted to mean conformational control of the binding entropy/free energy. We review long-established and recent cases of EEC and conclude that the large fluctuations in enthalpy and entropy observed are too great to be a result of only conformational changes and must result, to a considerable degree, from variations in the amounts of water immobilized or released on forming complexes. Changes in solvation can also contribute to EEC but this contribution is infrequently discussed. The conventional explanation for such enthalpy–entropy compensation (EEC) is that tighter contacts lead to a more negative enthalpy but increased molecular constraints, i.e., a compensating conformational entropy reduction. ![]() Structural modifications to interacting systems frequently lead to changes in both the enthalpy (heat) and entropy of the process that compensate each other, so that the Gibbs free energy is little changed: a major barrier to the development of lead compounds in drug discovery.
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