Explain why the folded structure is more thermodynamically favored (i.e., stable) in an aqueous environment than the unfolded structure.

Answer 1

Features that make the folded structure of a protein more thermodynamically stable:

1. Hydrogen bonding interactions (as occur in secondary structures such as α helices and β sheets) are energetically stabilizing, favorably lowering the enthalpy of the protein.
2. Burying nonpolar side chains of the protein minimizes entropically destabilizing hydrophobic interactions. Although folding the protein into a more organized structure might appear, at first glance, to be decreasing entropy (which is unfavorable) it gives the water molecules that are released from the duty of solvating nonpolar side chains translational freedom which leads to an overall increase in entropy of the system (which is favorable).

I think these are the two main features that provide the driving force for protein folding.

Answer 2

There are several reasons why the folded structure of a protein is more stable than the unfolded structure. Probably the most important of which is that the folded structure always has low energy and low entropy, and this is thermodynamically favorable.