The thermodynamic study of protein folding shows the generation of a narrow range of DG° values, as a net result of large changes in the DH° and TDS° values of the folding process. The obvious consequence of this narrow range of values is that a linear enthalpy–entropy relationship, showing apparent enthalpy–entropy compensation (EEC), is clearly observed to be associated with the study of protein folding. Herein, we show the DH°, TDS°, and DG° values for a set of 583 data from protein folding processes, at various temperatures, as calculated by using the Gibbs–Helmholtz equations. This set of thermodynamic data was calculated from the melting temperature (Tm), the melting enthalpy (DHm), and the change in heat capacity (DCp°) values, all of them associated with the heat-induced protein unfolding processes and included in the ProTherm Data Base. The average values of enthalpy (DH°av), entropy (TDS°av), and free energy (DG°av) for the folding process were calculated within the range of temperature from 0 °C to the average value of Tm. The values and temperature dependency of TDS°av within this temperature range are practically equal to those corresponding to DH°av, while DG°av remains small and displaying a curve with a minimum at about 10 °C and a value of DG° = −30.9 kJ/mol at the particular temperature of 25 °C. The large negative value of TDS°av, together with the also large and negative value of DCp°av, suggests large conformational changes and important EEC, thus causing the small average value of DG° for protein folding, which is enough to guarantee both protein stability and molecular flexibility to allow for adaptation to the chemical potentials of the environment. Our analysis suggests that EEC may be the quantum-mechanical evolutive mechanism to make functional proteins adaptative to environmental temperature and metabolite concentrations. The analysis of protein folding data, compared with those of protein–ligand interaction, allows us to suggest strategies to overcome EEC in the design of new drugs.
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