Using Implicit-Solvent Potentials to Extract Water Contributions to Enthalpy-Entropy Compensation in Biomolecular Associations

Biomolecular assemblytypically exhibits enthalpy-entropycompensation (EEC) behavior whose molecular origin remains a long-standingpuzzle. While water restructuring is believed to play an importantrole in EEC, its contribution to the entropy and enthalpy changes,and how these changes relate to EEC, remains poorly understood. Here,we show that water reorganization entropy/enthalpy can be obtainedby exploiting the temperature dependence in effective, implicit-solventpotentials. We find that the different temperature dependencies inthe hydrophobic interaction, rooted in water reorganization, resultin substantial variations in the entropy/enthalpy change, which areresponsible for EEC. For lower-critical-solution-temperature association,water reorganization entropy dominates the free-energy change at theexpense of enthalpy; for upper-critical-solution-temperature association,water reorganization enthalpy drives the process at the cost of entropy.Other effects, such as electrostatic interaction and conformationchange of the macromolecules, contribute much less to the variationsin entropy/enthalpy.