Entropy-enthalpy compensation: Fact or artifact?

The phenomenon of entropy-enthalpy (S-H) compensation is widely invoked as an explanatory principle in thermodynamic analyses of proteins, ligands, an d nucleic acids. It has been suggested that this compensation is an intrins ic property of either complex, fluctuating, or aqueous systems. The questio ns examined here are whether the observed compensation is extra-thermodynam ic (i.e., reflects anything more than the well-known laws of statistical th ermodynamics) and if so, what does it reveal about the system? Compensation is rather variably defined in the literature and different usages are disc ussed. The most precise and interesting one, which is considered here, is a linear relationship between DeltaH and DeltaS for some series of perturbat ions or changes in experimental variable. Some recent thermodynamic data on proteins purporting to show compensation is analyzed and shown to be bette r explained by other causes. A general statistical mechanical model of a co mplex system is analyzed to explore whether and under what conditions extra thermodynamic compensation can occur and what it reveals about the system. This model shows that the most likely behavior to be seen is linear S-H com pensation over a rather limited range of perturbations with a compensation temperature Tc = d DeltaH/d DeltaS within 20% of the experimental temperatu re. This behavior is insensitive to the details of the model, thus revealin g little extra-thermodynamic or causal information about the system. In add ition, it will likely be difficult to distinguish this from more trivial fo rms of compensation in real experimental systems.