Extent of enthalpy–entropy compensation in protein–ligand interactions

Authors

  • Tjelvar S. G. Olsson,

    1. Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London WC1E 6BT, United Kingdom
    Current affiliation:
    1. Tjelvar S. G. Olsson's current address is Cambridge Crystallographic Data Centre, Cambridge, CB2 1EZ, UK
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  • John E. Ladbury,

    1. Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London WC1E 6BT, United Kingdom
    Current affiliation:
    1. John E. Ladbury's current address is Department of Biochemistry and Molecular Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
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  • Will R. Pitt,

    1. UCB Celltech, Slough SL1 3WE, United Kingdom
    2. Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom
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  • Mark A. Williams

    Corresponding author
    1. Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, London WC1E 7HX, United Kingdom
    • Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK
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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.

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