Heat capacity changes and hydrophobic interactions in the binding of FK506 and rapamycin to the FK506 binding protein.

Abstract

Hydrophobic interactions, believed to be important determinants of the stability of many protein structures, multisubunit protein complexes, and protein/ligand complexes, may be considered to be the result of two component interaction processes: the removal of nonpolar groups from water (hydration) and the packing of these groups within proteins or protein complexes. Early studies by Kauzmann (8) and Tanford (9) emphasized the similarities of protein unfolding and the transfer of nonpolar substances from water to nonpolar phases. More recently, striking correlations between the thermodynamics of protein folding and the aqueous dissolution of hydrophobic substances have been noted by Sturtevant (10), Baldwin (11), and Murphy et al. (12). Among the most intriguing of the observations are the linear relationships observed between (i) enthalpy and heat capacity changes and (ii) entropy and heat capacity changes, for solutes within a given class (gaseous, solid, or liquid hydrophobic compound or protein). Consideration of these relationships has led to differing theories regarding the contribution of hydrophobic interactions to the stabilization of protein structures (11, 13, 14). A key common feature of the theories is the dissection of the free energy of unfolding into its various contributions, with the heat capacity playing a central role in determining the free energy of hydrophobicinteraction.An early analysis by Sturtevant (10) indicated that heat capacity changes for protein unfolding are determined largely by the exposure of nonpolar groups to water but that one must also consider contributions due to the changes in the numbers of easily excitable vibrational modes upon unfolding. The concept of solvent-accessible surface area introduced by Lee and Richards (15) provided an important structural parameter with which to describe the interaction of water with proteins. Recently, several reports have focused on the relationship between heat capacity changes and changes in solvent-accessible surface areas accompanying protein unfolding. Spolar et al. (16) and Livingstone et al. (17) analyzed the heat capacity changes for the unfolding of proteins for which high-resolution x-ray crystallographic information was available. Their analyses indicated that the heat capacity change for unfolding proteins is proportional to the difference in solvent-accessible nonpolar surface area between native and denatured states. Another investigation on the binding of various S peptides to S protein casts doubt on the generalization of the relationship between nonpolar surface and heat capacity (18,19).To clarify the structural determinants for heat capacities and their relationship to the free energy of hydrophobic interaction, it is important to obtain high-precision measurements of heat capacity changes, in addition to other thermotTo whom reprint requests should be addressed. 4781The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertis...

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