Rationalization of Solvent-Mediated Enthalpy-Entropy Compensation with the Gibbs-Helmholtz Equation

This review examines the effect of solvent involvement in protein-ligand interactions on the extent of conformity with the Gibbs-Helmholtz equation, which was based on assumed inertness of the solvent-an assumption that rendered possible the evaluation of ΔH^o and TΔS^o by employing the integrated form of the van't Hoff isochore. Conformity with the Gibbs-Helmholtz equation is retained in situations where there is temperature dependence of the calorimetrically measured standard enthalpy change despite no change in standard free energy change (ΔΔG^o ≈ 0). Before the advent of isothermal titration calorimetry this situation was taken to signify that ΔH^o = 0 rather than (ΔH^o)_vH = 0, whereupon (ΔG^o)_vH = (TΔS^o)_vH. In isothermal titration calorimetry the measured standard enthalpy change (ΔH^o)_cal is a thermodynamic parameter for the whole system, whereupon values of (TΔS^o)_cal calculated as (ΔH^o)_cal-(ΔG^o)_vH include the van't Hoff enthalpy contribution (ΔH^o)_vH. A sufficiently large magnitude for that van't Hoff contribution leads to a Gibbs-Helmholtz plot with a slope greater than unity. A similar situation arises in systems exhibiting a slight but significant dependence of (ΔG^o)_vH upon (ΔH^o)_cal -examples of systems exhibiting substantial rather than extreme enthalpy-entropy compensation.