Solvent reorganization leads to enthalpy–entropy compensation in biomolecular recognition

In aqueous solutions at room temperature, the association between two macromolecules (such as protein–protein and protein–ligand binding) exhibits enthalpy–entropy compensation (EEC) behavior: While the overall binding Gibbs free energy remains nearly constant, there is great variation in the entropic and enthalpic contributions, depending on the species of the paired polymers. The molecular origin of the EEC remains controversial. Here, using coarse-grained simulations and thermodynamics analysis, we extract the entropic and enthalpic components in the thermodynamic driving forces for the association between two biomolecules. We find that the solvent reorganization is the major source of the EEC during the binding process, arising from the temperature-dependent nonelectrostatic and electrostatic interactions. For systems with a lower critical solution temperature (LCST) below the room temperature, the solvent reorganization entropically dominates the favorable free energy change in the nonelectrostatic interaction, at the expense of energy. For systems with an upper critical solution temperature (UCST) above the room temperature, the nonelectrostatic part of the free energy change is dominated by the energy due to solvent reorganization, at the expense of entropy. The solvent reorganization due to the electrostatic attraction also has EEC behavior: The entropic and enthalpic contributions to the free energy change are of opposite signs.