When a polypeptide is in its native conformation, there are weak interactions between its R groups. However, when it is denatured there are similar interactions between the protein groups and water. What then accounts for the greater stability of the native conformation?

In the unfolded polypeptide, there are ordered solvation shells of water around the protein

groups. The number of water molecules involved in such ordered shells is reduced when the protein

folds, resulting in higher entropy. Hence, the lower free energy of the native conformation.