The osmophobic effect: Natural selection of a thermodynamic force in protein folding

Intracellular organic osmolytes are present in certain organisms adapted to harsh environments and these osmolytes protect intracellular macromolecule s against the denaturing environmental stress. In natural selection of orga nic osmolytes as protein stabilizers, it appears that the osmolyte property selected for is the unfavorable interaction between the osmolyte and the p eptide backbone, a solvophobic thermodynamic force that we call the osmopho bic effect. Because the peptide backbone is highly exposed to osmolyte in t he denatured state, the osmophobic effect preferentially raises the free en ergy of the denatured state, shifting the equilibrium in favor of the nativ e state. By focusing the solvophobic force on the denatured state, the nati ve state is left free to function relatively unfettered by the presence of osmolyte. The osmophobic effect is a newly uncovered thermodynamic force in nature that complements the well-recognized hydrophobic interactions, hydr ogen bonding, electrostatic and dispersion forces that drive protein foldin g. In organisms whose survival depends on the intracellular presence of osm olytes that can counteract denaturing stresses, the osmophobic effect is as fundamental to protein folding as these well-recognized forces. (C) 2001 A cademic Press.