Extent of enthalpy–entropy compensation in protein–ligand interactions
Open Access
- 7 July 2011
- journal article
- research article
- Published by Wiley in Protein Science
- Vol. 20 (9), 1607-1618
- https://doi.org/10.1002/pro.692
Abstract
The extent of enthalpy–entropy compensation in protein–ligand interactions has long been disputed because negatively correlated enthalpy (ΔH) and entropy (TΔS) changes can arise from constraints imposed by experimental and analytical procedures as well as through a physical compensation mechanism. To distinguish these possibilities, we have created quantitative models of the effects of experimental constraints on isothermal titration calorimetry (ITC) measurements. These constraints are found to obscure any compensation that may be present in common data representations and regression analyses (e.g., in ΔH vs. –TΔS plots). However, transforming the thermodynamic data into ΔΔ-plots of the differences between all pairs of ligands that bind each protein diminishes the influence of experimental constraints and representational bias. Statistical analysis of data from 32 diverse proteins shows a significant and widespread tendency to compensation. ΔΔH versus ΔΔG plots reveal a wide variation in the extent of compensation for different ligand modifications. While strong compensation (ΔΔH and −TΔΔS opposed and differing by < 20% in magnitude) is observed for 22% of modifications (twice that expected without compensation), 15% of modifications result in reinforcement (ΔΔH and −TΔΔS of the same sign). Because both enthalpy and entropy changes arise from changes to the distribution of energy states on binding, there is a general theoretical expectation of compensated behavior. However, prior theoretical studies have focussed on explaining a stronger tendency to compensation than actually found here. These results, showing strong but imperfect compensation, will act as a benchmark for future theoretical models of the thermodynamic consequences of ligand modification.Keywords
Funding Information
- UCB Celltech
This publication has 26 references indexed in Scilit:
- Higher throughput calorimetry: opportunities, approaches and challengesCurrent Opinion in Structural Biology, 2010
- The Thermodynamics of Protein–Ligand Interaction and Solvation: Insights for Ligand DesignJournal of Molecular Biology, 2008
- PDBcal: A Comprehensive Dataset for Receptor–Ligand Interactions with Three‐dimensional Structures and Binding Thermodynamics from Isothermal Titration CalorimetryChemical Biology & Drug Design, 2008
- Enthalpy−Entropy Compensation Reveals Solvent Reorganization as a Driving Force for Supramolecular Encapsulation in WaterJournal of the American Chemical Society, 2008
- The Paradoxical Thermodynamic Basis for the Interaction of Ethylene Glycol, Glycine, and Sarcosine Chains with Bovine Carbonic Anhydrase II: An Unexpected Manifestation of Enthalpy/Entropy CompensationJournal of the American Chemical Society, 2006
- Entropy—enthalpy compensation: Fact or artifact?Protein Science, 2001
- Entropy−Enthalpy Compensation in Solvation and Ligand Binding RevisitedJournal of the American Chemical Society, 1998
- Win some, lose some: enthalpy-entropy compensation in weak intermolecular interactionsCell Chemical Biology, 1995
- Application of a generalised enthalpy–entropy relationship to binding co-operativity and weak associations in solutionJournal of the Chemical Society, Perkin Transactions 2, 1995
- Enthalpy-entropy compensation. 2. Separation of the chemical from the statistical effectThe Journal of Physical Chemistry, 1976