Stability of folded conformations

Significant advances have been made in understanding the thermodynamics of the hydrophobic effect and of the reversible unfolding of proteins, although there is still considerable controversy. Recent analyses suggest that the predominant factor in stabilizing the folded states of proteins is intramolecular hydrogen bonding even though in the unfolded state the polar groups form intermolecular hydrogen bonds with water. Van der Waals interactions between non-polar groups also contribute substantially, but perhaps not as much as might have been expected if protein interiors were perfectly close-packed. The role of the solvent seems to be primarily destabilizing, and involves the favourable solvation of both polar and non-polar groups. The effects of added stabilizers and denaturants can be understood on the basis of their alterations of the properties of water and of their interactions with the surfaces of folded and unfolded proteins. Also, the electrostatic interactions between groups involved in salt bridges in folded proteins can be substantial.