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Published August 3, 2023 | v1
Journal Article Open

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

  • 1. ROR icon California Institute of Technology


Biomolecular assembly typically exhibits enthalpy–entropy compensation (EEC) behavior whose molecular origin remains a long-standing puzzle. While water restructuring is believed to play an important role 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 obtained by exploiting the temperature dependence in effective, implicit-solvent potentials. We find that the different temperature dependencies in the hydrophobic interaction, rooted in water reorganization, result in substantial variations in the entropy/enthalpy change, which are responsible for EEC. For lower-critical-solution-temperature association, water reorganization entropy dominates the free-energy change at the expense 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 conformation change of the macromolecules, contribute much less to the variations in entropy/enthalpy.

Copyright and License

© 2023 The Authors. Published by American Chemical Society. Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).


This research was supported by funding from Hong Kong Quantum AI Lab, AIR@InnoHK of the Hong Kong Government. This research used the Theory and Computation facility of the Center for Functional Nanomaterials (CFN), which is a U.S. Department of Energy Office of Science User Facility, at the Brookhaven National Laboratory under Contract no. DE-SC0012704.

Attached Files

jp3c03799.pdf - published article

jp3c03799_si_001.pdf - supplemental information



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Additional details

October 25, 2023
October 25, 2023