ENTHALPY CHANGE IN PROTEIN-FOLDING AND BINDING - REFINEMENT OF PARAMETERS FOR STRUCTURE-BASED CALCULATIONS

Two effects are mainly responsible for the observed enthalpy change in protein unfolding: the disruption of internal interactions within the protein molecule (van der Waals, hydrogen bonds, etc.) and the hydrat ion of the groups that are buried in the native state and become expos ed to the solvent on unfolding. In the traditional thermodynamic analy sis, the effects of hydration have usually been evaluated using the th ermodynamic data for the transfer of small model compounds from the ga s phase to water, The contribution of internal interactions, on the ot her hand, are usually estimated by subtracting the hydration effects f rom the experimental enthalpy of unfolding. The main drawback of this approach is that the enthalpic contributions of hydration, and those d ue to the disruption of internal interactions, are more than one order of magnitude larger than the experimental enthalpy value, The enthalp y contributions of hydration and disruption of internal interactions h ave opposite signs and cancel each other almost completely resulting i n a final value that is over 10 times smaller than the individual term s. For this reason, the classical approach cannot be used to accuratel y predict unfolding enthalpies from structure: any error in the estima tion of the hydration enthalpy will be amplified by a factor of 10 or more in the estimation of the unfolding enthalpy. Recently, it has bee n shown that simple parametric equations that relate the enthalpy chan ge with certain structural parameters, especially changes in solvent a ccessible surface areas have considerable predictive power. In this pa per, we provide a physical foundation to that parametrization and in t he process we present a system of equations that explicitly includes t he enthalpic effects of the packing density between the different atom s within the protein molecule. Using this approach, the error in the p rediction of folding/unfolding enthalpies at 60 degrees C, the median temperature for thermal unfolding, is better than +/-3% (standard devi ation = 4 kcal/mol), (C) 1996 Wiley-Liss, Inc.