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Protein folding thermodynamics

  1. Oct 3, 2004 #1
    My textbook’s explanation for spontaneous renaturation of defolded protein is this:

    “Although in defolded state protein has grater entropy, greater degree of disorder, it folds into original conformation (lower entropy), and this seems to be in collision with the II law of thermodynamics. But by refolding molecules of water surrounding him increase its own entropy by forming maximum number of hydrogen bonds (they’re squeezing, pushing in hydrophobic regions from protein surface inside of protein, allowing hydrophilic regions to come out to surface to form H-bonds with water), so net change in entropy of solute and protein is than increase of entropy, and process is spontaneous.”

    Thing that I disagree in this that by forming hydrogen bonds water is increasing its own entropy, how can this be true ?
    By forming maximum number of (or generally forming) hydrogen bonds water increases its order, by organizing own molecules in ordered fashion dictated by hydrogen bonds. Than how can this H-bond forming could be S increasing?

    Please help.

    p.s. Sorry for posting in two rooms, but because of type of this massage bio/physics, I think that’s the way I’ll get best (or any:)) answers
  2. jcsd
  3. Oct 3, 2004 #2
    There is more to deal with in a system than entropy alone. Look at the Gibbs free energy equation.

    Besides, the second law was never intended to deal with what happens inside a system only what happens to the system as a whole. It states that the NET movement must be static or toward entropy.

    This sounds like an argument from a creationist.

  4. Oct 4, 2004 #3

    Another God

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    There is more to protein folding than just entropy states. If protein folding was spontaneous, then allowing a cooked egg to cool down again would have the egg turn back into a runny state as the proteins all renatured.

    It has a lot to do with chaperone proteins assisting the process and other stuff which I can't think of right now off the top of my head.
  5. Oct 4, 2004 #4
    OK, I agree with your remarks. But those aren’t answers to my question.

    Of course not all denaturized proteins will be able to refold spontaneously, some will, and some will use chaperones, but some will do this without any help (you must know about Anfinsen’s classical experiments with denaturized RNase, that in more than 90% cases folds again to active state without any help).

    dG = dH - TdS (and consider protein with surrounding water observed system)

    But how do you explain spontaneous refolding ?
    Only way spontaneous refolding could happen is decrease of free energy of the system. And it is obvious how this can be done considering this equation.
    You have to increase S or have negative dH. What mechanism you propose for this change?
  6. May 22, 2010 #5


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    Think about it in terms of surface area. A folded protein has less surface area. We know that water forms an ordered solvation shell around the protein. So if the ordered shell has less molecules in it (as it would for a folded protein, since a folded protein has less surface area than an unfolded one) then we can assume the water gains entropy (ie, more water molecules are in the bulk, which is less ordered).
  7. May 24, 2010 #6
    Your remark here is absolutely correct, the protein must minimizes its structural free energy.
    Enthalpy is just important as entropy in this respect.

    The simplest microscopic (i.e. statistical mechanical) description of protein folding free energy is probably the so-called HP model. I found a technical summary here for example.

    The explanation given by the textbook you mentioned earlier seems a bit confusing.
    Have you checked out the textbook called 'Molecular Driving Forces' by Ken A. Dill?
    That is really clear...
    Last edited by a moderator: Apr 25, 2017
  8. Aug 4, 2012 #7
    Hydrophobic effect is the major force in protein folding.
    Non-polar side chains can't form H bonds around them. The water molecules form ice-like "cages" around these side chains, resulting in a loss of entropy if these side chains are solvent exposed.

    Clustering of these side chains reduces this entropic loss (fewer water molecules in a ice-like state). These side chains thus prefer to cluster or get buried into the interior of the protein in "hydrophobic cores"

    This can be energetically quite favorable; the burial of a single -CH2 group has a delta G of about -1 kcal/mol (close to energy of a H bond).

    I just took a class on protein and nucleic acid structure this last semester. I think hydrophobic effect/entropy was the answer to nearly every question on the exams lol
  9. Aug 4, 2012 #8
    Check the dates when responding. The last post before yours in this thread was over 2 years ago. The participants are unlikely to respond to you. For what it's worth, the OP was saying protein folding violates of the second law of thermodynamics. Life itself "violates" the second law if you consider a living organism as a closed system. Living systems are not closed systems. Life represents a local "island" of lower entropy, but it raises the entropy of its environment so that overall entropy increases.
    Last edited: Aug 4, 2012
  10. Aug 4, 2012 #9
    yep there's plenty of cases of this cases where local entropy spontaneously decreases. the easiest non-bio example is the phase segregation of block copolymers. a single polymer chain of half hydrophobic monomers and half hydrophilic monomers will fold on itself in water solution such that the hydrophilic parts are exposed.

    a protein can be said to just be a highly complicated copolymer.
  11. Aug 4, 2012 #10
    I conjecture it is because the ambient water molecules form hydrogen bonds with each other. The water itself is in a low entropy state. When hydrogen bonds form between a water molecule and a protein, the hydrogen bonds of the water molecule with other water molecules break. Therefore, the entropy of the water increases when the protein spontaneously transforms into its original state.
    The water molecules have more degrees of freedom embedded in the protein then they have outside the protein. Suppose a water molecule forms one hydrogen bond with an amino acid residue, which results in it being completely surrounded by amino by the rest of the protein. The rest of the protein molecule geometrically shields this water molecule from other water molecules. At least the water molecule can rotate around that hydrogen bond. However, the same water molecule outside the protein may form two hydrogen bonds with another water molecule. This would inhibit rotation of both water molecules.
    In terms of rotation, water molecules may have more degrees of freedom inside a protein molecule "cage" then outside with other water molecules. The more degrees of freedom, the more entropy.
    You didn't mention what conditions are necessary for the protein to spontaneously transforms back to its original state. My conjecture is that the conditions are such that the entropy density of the ambient water is particularly low.
    Maybe "spontaneous renaturation" is more likely in the temperature range where water expands with cooling. For instance, water expands with decreasing temperature at temperatures close to the freezing point of water. This is why pipes burst in winter. The formation of hydrogen bonds between water molecules results in a crystalline form with gaps in it. Thus, the water molecules are seriously constrained by their mutual interaction at temperatures close to the freezing point. A protein molecule, by absorbing water molecules, may break up the crystalline structure of the water. Thus, spontaneous renaturing may be particularly more likely in this temperature range.
    This is my conjecture, made to show you that water is not always "disorderly". You have to consider the structure of the "free" water in addition to the structure of the protein.
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