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

Abstract

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.

Gibbs Free Energy and Enthalpy–Entropy Compensation in Protein–Ligand Interactions

“…The plot shows the kind of behavior usually denoted as an enthalpy-entropy compensation (EEC). This type of behavior has been repeatedly reported for more than fifty years in many experiments closely associated with protein-ligand interactions in water solution [6][7][8]10,[31][32][33][34][35][36]. As can be observed in part B of the same figure, it is accompanied by the lack of correlation of ∆H • vs. ∆G • , which is, in turn, usually found in chemical transformations, mostly in gaseous phase, and having a simple stoichiometry similar to that of a simple protein-ligand interaction.…”

“…A linear enthalpy-entropy relationship is frequently associated with thermodynamic protein-ligand interactions [1][2][3][4][5][6][7][8]. When the reaction enthalpy values, ∆H • , associated with any particular set of ligand-protein interactions are plotted against the corresponding changes in entropy values, T∆S • , a straight line with a slope close to 1 is usually obtained.…”

“…The development of ITC microcalorimeters, however, allows measuring enthalpy values with a precision high enough to discard experimental errors. The apparent enthalpy-entropy compensation (EEC) is an observable fact, although its molecular origin still remains controversial and hard to understand [6,8,10]. Herein, we want to present a plausible explanation to unveil its origin within the framework of contributing to those studies concerned with the design and discovery of new drugs having a higher affinity for their targets.…”

Entropy Drives Interpolymer Association in Water: Insights into Molecular Mechanisms

“…Any entropic changes due to solvent reorganization resulting from the bond are separate mechanisms that need to be understood. Recent MD simulations have shown that the reorganization of water drives the association of charged and uncharged polymers, − and this reorganization is also suggested as the main driving force for molecular recognition …”

Elucidating the Effect of Amine Charge State on Poly(β-amino ester) Degradation Using Permanently Charged Analogs

“…These electronic environment changes or amine-catalyzed ester hydrolysis (as has been proposed for other amine and ester containing polymers) − may underlie differences in polymer behavior as a function of charge state. Likely, some combination of these factors, local pH changes, , counterion condensation, , water organization changes, − local dielectric changes, electron distribution, and/or amine-catalyzed hydrolysis, − results in the faster degradation of PBAEs relative to their charged, quaternary analogs.…”