Entropy-Enthalpy Compensation May Be a Useful Interpretation Tool for Complex Systems Like Protein-DNA Complexes: An Appeal to Experimentalists

In various chemical systems enthalpy-entropy compensation (EEC) is a well-known rule of behavior, although the physical roots of it are still not completely understood. It has been frequently questioned whether EEC is a truly physical phenomenon or a coincidence due to trivial mathematical connections between statistical-mechanical parameters - or even simpler: A phantom effect resulting from the misinterpretation of experimental data. Here, we review EEC from a new standpoint using the notion of correlation which is essential for the method of factor analysis, but is not conventional in physics and chemistry. We conclude that the EEC may be rationalized in terms of hidden (not directly measurable with the help of the current experimental set-up) but physically real factors, implying a Carnot-cycle model in which a micro-phase transition (MPT) plays a crucial role. Examples of such MPTs underlying physically valid EEC should be typically cooperative processes in supramolecular aggregates, like changes of structured water at hydrophobic surfaces, conformational transitions upon ligand-biopolymer binding, and so on, so forth. The MPT notion could help rationalize the occurrence of EEC in connection with hydration and folding of proteins,enzymatic reactions, functioning of molecular motors, DNA de- and rehybridization, as well as similar phenomena.

💡 Research Summary

The paper tackles the long‑standing debate over entropy‑enthalpy compensation (EEC), a phenomenon in which changes in enthalpy (ΔH) and entropy (ΔS) for a process appear to be linearly correlated so that the free‑energy change (ΔG = ΔH − TΔS) remains relatively constant. While many experimental studies across chemistry and biophysics have reported such linear relationships, critics have argued that EEC may be a statistical artifact arising from limited temperature ranges, data fitting procedures, or experimental noise. The authors acknowledge these criticisms but contend that dismissing EEC as a phantom effect overlooks a deeper physical origin.

The central theoretical contribution is the introduction of a correlation‑based factor‑analysis framework. In this view, the observable thermodynamic quantities ΔH and ΔS are not independent; rather, they are linear combinations of one or more hidden variables that cannot be directly measured with standard calorimetric setups. Mathematically, the observed vector X =