We argue that upon the structural change of a protein, the gain or loss of the intramolecular energy is largely compensated by the loss or gain of the hydration energy, when the folding is considered under the isochoric condition. We introduce the sum of the intramolecular energy and the hydration free energy as the key function. The change in this function is governed by the change in the hydration entropy. A protein is designed to fold into the structure that maximizes the entropy of water under the requirement that sufficiently many intramolecular hydrogen bonds be formed to compensate the dehydration penalty. (c) 2006 Elsevier B.V. All rights reserved.