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

Abstract 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 Δ H o and T Δ S 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 (ΔΔ G o ≈ 0). Before the advent of isothermal titration calorimetry this situation was taken to signify that Δ H o = 0 rather than (ΔH o ) vH = 0, whereupon (Δ G o ) vH = ( T Δ S o ) vH . In isothermal titration calorimetry the measured standard enthalpy change (Δ H o ) cal is a thermodynamic parameter for the whole system, whereupon values of ( T Δ S o ) cal calculated as (Δ H o ) cal –(Δ G o ) vH include the van’t Hoff enthalpy contribution (Δ H 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 (Δ G o ) vH upon (Δ H o ) cal —examples of systems exhibiting substantial rather than extreme enthalpy–entropy compensation.