Entropy-enthalpy compensation in conjugated proteins

Entropy–enthalpy compensation is observed in many reactions, particularly for polymeric biomolecules that often involve large changes in entropy and enthalpy. The imperfect cancelation of entropy and enthalpy dictates many biophysical characteristics, such as protein thermodynamic stability and the free energy barrier for protein folding. In this study, we examine how tethering a conjugate to a protein may affect the thermodynamic stability of the protein. We found that a conjugate mostly affects the unfolded state by eliminating formation of some residual interactions. Consequently, both the enthalpy and the entropy of the unfolded state are affected. We suggest that, because this effect is not localized, the gain in conformational flexibility (i.e., increased entropy) is larger than the loss of some residual interaction (i.e., increased enthalpy). Therefore, the unfolded state of the conjugated protein has a lower free energy than that of the free protein, resulting in thermodynamic destabilization.