Protein Stability: Folded or Unfolded?

[lha08]

Homework Statement

I'm a little confused as to which conformation of protein is more stable (folded or unfolded)...like in my book it says that the most stable (lowest free energy) is the one with the maximum number of weak interactions...so in this case, shouldn't it be the folded one? but on the other hand, it says that the unfolded states have high degree of conformational entropy and high free energy...so its the least stable? Am I correct in my logic or am i missing something?
thanks

Homework Equations

The Attempt at a Solution

 

[Ygggdrasil]

There are two components to thermodynamic stability: enthalpy (a measure of the chemical potential energy from chemical bonds and non-covalent interactions) and entropy (a measure of the disorder of the system). You are correct to note that the folded state is generally enthalpically favored because it contains many more non-covalent interactions that help to lower the overall energy of the protein. It is also correct that the unfolded state is generally entropically favored* because many more conformations are accessible to the unfolded state than the folded state.

So, which state, the folded state or unfolded state, is favored? The answer depends on whether the enthalpic contributions to stability or the entropic contributions to stability matter more. This balance, as it turns out, depends on the temperature (this is a consequence of the definition of free energy). At high temperatures, it is favorable to increase entropy even at the expense of breaking favorable interactions. Conversely, at low temperatures, it is favorable to lower entropy by forming interactions even at the expense of decreasing entropy.

A good everyday example of this principle is the melting/freezing of water. Ice has stronger interactions between water molecules than liquid water but liquid water has higher entropy. Therefore, at low temperatures, ice is favored and water freezes while at high temperatures, water is favored and ice melts. A similar situation occurs with proteins. At low temperatures, the folded state is thermodynamically favored, but high temperatures can cause proteins to favor the unfolded state.


*N.B. sometimes the folded state can actually be entropically favored because of the hydrophobic effect. Basically, hydrophobic regions cause the water dissolving the hydrophobic regions to be more ordered than normal water. Therefore, hiding hydrophobic amino acids in the interior of proteins prevents water from having to form ordered solvation shells around the protein and the folded state is entropically favored over the unfolded state. In this case, high temperatures can still cause the protein to unfold but for different reasons. The high temperatures allow transient exposure of the hdyrophobic core of the protein and the hydrophobic cores of nearby proteins can come together to form aggregates.