Question

1. The Levinthal paradox revealed that it would be impossible for proteins to fold up into their native structure in a biological meaningful timeframe if they were required to search all available conformational space. Name two early events in protein folding that enable proteins to limit the conformational space they need to sample to find their native conformation.
2. There is a dramatic decrease in the entropy of a protein during the course of protein folding. Does this process disobey the Second Law of Thermodynamics? Explain your answer.

Biochem Questions

Answer 1

Protein folding is a highly complex process by which proteins are folded into their biochemically functional three-dimensional forms. The hydrophobic force is an important driving force behind protein folding. The polar side chains are usually directed towards and interact with water, while the hydrophobic core of the folded protein consists of non-polar side chains. Other forces that are favorable for protein folding are the formation of intramolecular hydrogen bonds and van der Waals forces.

Protein folding is entropically unfavorable because it minimizes the dispersal of energy and adds order to the system. However, the summation of the hydrophobic effect, hydrogen bonding, and van der Waals forces is greater in magnitude than the loss of entropy. Protein folding is therefore a spontaneous process because the sign of ΔG (Gibbs free energy) is negative.

Hydrophobic domains of a protein constrain the possible configurations of surrounding water (see explanation above), and so their burial upon folding increases the water’s entropy. Moreover, it turns out that the hydrogen bonding of polar residues and the backbone is satisfied both in an unfolded state (by water) and in a folded state (by each other). Therefore enthalpy is “zero sum,” and protein folding is driven almost entirely by entropy.