Journal of Biosciences

, Volume 42, Issue 4, pp 665–670 | Cite as

Enthalpy–entropy compensation and the isokinetic temperature in enzyme catalysis

  • Athel Cornish-Bowden


Enthalpy–entropy compensation supposes that differences in activation enthalpy ∆H for different reactions (or, typically in biochemistry, the same reaction catalysed by enzymes obtained from different species) may be compensated for by differences in activation entropy ∆S . At the isokinetic temperature the compensation is exact, so that all samples have the same activity. These ideas have been controversial for several decades, but examples are still frequently reported as evidence of a real phenomenon, nearly all of the reports ignoring or discounting the possibility of a statistical artefact. Even for measurements in pure chemistry artefacts occur often, and they are almost inescapable in enzyme kinetics and other fields that involve biological macromolecules, on account of limited stability and the fact that kinetic equations are normally valid only over a restricted range of temperature. Here I review the current status and correct an error in a recent book chapter.


Arrhenius equation compensation enthalpy entropy isokinetic temperature 



This work was supported by Centre National de la Recherche Scientifique and by Aix-Marseille Université. I thank María Luz Cárdenas for useful discussions and Mark Bushuev for shedding helpful light on his paper on spin transitions in an Fe(II) complex.


  1. Barrie PJ 2012 The mathematical origins of the kinetic compensation effect: 1. The effect of random experimental errors. Phys. Chem. Chem. Phys. 14 318–326CrossRefPubMedGoogle Scholar
  2. Bushuev MB, Pishchur DP, Nikolaenkovac EB and Krivopalov VP 2016 Compensation effects and relation between the activation energy of spin transition and the hysteresis loop width for an iron(II) complex. Phys. Chem. Chem. Phys. 18 16690–16699CrossRefPubMedGoogle Scholar
  3. Chang Y, Lai JY and Lee DJ 2016 Thermodynamic parameters for adsorption equilibrium of heavy metals and dyes from wastewaters: research updated. Biores. Technol. 222 513–516CrossRefGoogle Scholar
  4. Constable F 1925 The mechanism of catalytic decomposition. Proc. Roy. Soc. Lond. A 108 355–378CrossRefGoogle Scholar
  5. Cooper A, Johnson CM, Lakey JH and Nöllmann M 2001 Heat does not come in different colours: entropy–enthalpy compensation, free energy windows, quantum confinement, pressure perturbation calorimetry, solvation and multiple causes of heat capacity effects in biomolecular interactions. Biophys. Chem. 93 215–230CrossRefPubMedGoogle Scholar
  6. Cornish-Bowden A 2002 Enthalpy–entropy compensation: a phantom phenomenon. J. Biosci. 27 121–126CrossRefPubMedGoogle Scholar
  7. Cornish-Bowden A 2012a Enthalpy–entropy compensation as deduced from measurements of temperature dependence; in H Gohlke (ed.) Protein-ligand interactions (Weinheim: Wiley-VCH) pp 33–43CrossRefGoogle Scholar
  8. Cornish-Bowden A 2012b Fundamentals of enzyme kinetics 4th edition (Weinheim: Wiley-VCH) pp 436–438Google Scholar
  9. Cornish-Bowden A 2016 Biochemical evolution: the pursuit of perfection (New York: Garland Science) pp 114–121Google Scholar
  10. Exner O 1964 On the enthalpy–entropy relationship. Coll. Czech. Chem. Comm. 26 1094–1113CrossRefGoogle Scholar
  11. Exner O 1972 Statistics of enthalpy–entropy relationship. 1. Special case. Coll. Czech. Chem. Comm. 37 1425–1444CrossRefGoogle Scholar
  12. Exner O 1973 Statistics of enthalpy–entropy relationship. 3. Processing of calorimetric data. Coll. Czech. Chem. Comm. 38 799–812CrossRefGoogle Scholar
  13. Exner O 1997 How to get wrong results from good experimental data: a survey of incorrect applications of regression. J. Phys. Org. Chem. 10 797–813CrossRefGoogle Scholar
  14. Exner O and Beranek V 1973 Statistics of enthalpy–entropy relationship. 2. General case. Coll. Czech. Chem. Comm. 38 781–798CrossRefGoogle Scholar
  15. Gutfreund H 1995 Kinetics for the life sciences (Cambridge: Cambridge University Press) pp 246–248CrossRefGoogle Scholar
  16. Johansen G and Lumry R 1961 Statistical analysis of enzymic steady-state rate data. C.R. Trav. Lab. Carlsberg 32 185–214Google Scholar
  17. Johnston IA and Goldspink G 1975 Thermodynamic activation parameters of fish myofibrillar ATPase enzyme and evolutionary adaptations to temperature. Nature 237 620–622CrossRefGoogle Scholar
  18. Keszei E 2016 Gibbs-Helmholtz equation and entropy. Chemtexts 2 15CrossRefGoogle Scholar
  19. Krug RR 1976 Statistical interpretation of enthalpy–entropy compensation. Nature 261 566–567CrossRefGoogle Scholar
  20. Krug RR, Hunter WG and Grieger RA 1976a Enthalpy–entropy compensation. 1. Some fundamental statistical problems associated with analysis of Van’t Hoff and Arrhenius data. J. Phys. Chem. 80 2335–2341CrossRefGoogle Scholar
  21. Krug RR, Hunter WG and Grieger RA 1976b Enthalpy–entropy compensation. 2. Separation of chemical from statistical effect. J. Phys. Chem. 80 2341–2351CrossRefGoogle Scholar
  22. Leffler JE 1965 Concerning the isokinetic relationship. Nature 205 1101–1102CrossRefGoogle Scholar
  23. Lumry R and Rajender S 1970 Enthalpy–entropy compensation phenomena in water solutions of proteins and small molecules: a ubiquitous property of water. Biopolymers 9 1125–1227CrossRefPubMedGoogle Scholar
  24. Lumry R and Rajender S 1971 Studies of chymotrypsinogen family of proteins. 16. Enthalpy–entropy compensation phenomenon of α-chymotrypsin and temperature of minimum sensitivity. J. Phys. Chem. 75 1387–1401CrossRefGoogle Scholar
  25. Moss RA 2017 Adventures in reactive intermediate chemistry: a perspective and retrospective. J. Org. Chem. 82 2307–2318CrossRefPubMedGoogle Scholar
  26. Olsson TSG, Ladbury JE, Pitt WR and Williams MA 2011 Extent of enthalpy–entropy compensation in protein-ligand interactions Protein Sci. 20 1607–1618CrossRefPubMedPubMedCentralGoogle Scholar
  27. Ouvrard C, Berthelot M, Lamer T and Exner O 2001 A program for linear regression with a common point of intersection: the isokinetic relationship. J. Chem. Info. Comput. Sci. 41 1141–1144CrossRefGoogle Scholar
  28. Pan A, Kar T, Rakshit AK and Moulik SP 2016 Enthalpy-entropy compensation (EEC) effect: decisive role of free energy. J. Phys. Chem. B 120 10531–10539CrossRefGoogle Scholar
  29. Perez-Benito JF and Mulero-Raichs M 2016 Enthalpy–entropy compensation effect in chemical kinetics and experimental errors: a numerical simulation approach. J. Phys. Chem. A 120 7598–7609CrossRefPubMedGoogle Scholar
  30. Piguet C 2011 Enthalpy–entropy correlations as chemical guides to unravel self-assembly processes. Dalton Trans. 40 8059–8071CrossRefPubMedGoogle Scholar
  31. Sharp K 2001 Entropy–enthalpy compensation: fact or artifact? Prot. Sci. 10 661–667CrossRefGoogle Scholar
  32. Singh RK, Suzuki T, Mandal T, Balsubramanian N, Haldar M, Mueller DJ, Strode JA, Cook G, Mallik S and Srivastava DK 2014 Thermodynamics of binding of structurally similar ligands to histone deacetylase 8 sheds light on challenges in the rational design of potent and isozyme-selective inhibitors of the enzyme. Biochemistry 53 7445–7458CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Indian Academy of Sciences 2017

Authors and Affiliations

  1. 1.Aix Marseille Univ, CNRS, BIP, IMMMarseilleFrance

Personalised recommendations