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Protein folding

  1. Jun 23, 2008 #1
    I have a question about protein folding. I have heard that there is a free energy barrier to overcome in going from the unfolded (ensemble) to folded states, and that this barrier is largely entropic -- i.e., as the (idealized, general) protein starts to fold, it loses more in entropy than it gains (loses) in enthalpy. If so, then why does the protein take these steps (of going from the unfolded to the transition state) spontaneously in the first place?
  2. jcsd
  3. Jun 23, 2008 #2


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    Are you familiar with chaperone proteins? These proteins are implicated in the folding mechanism of nascent unfolded protein segments. It may require energy to correctly fold a protein in the cytosol... it may not be merely a thermodynamic inevitability.

    The chaperones GroES and GroEL require 14 ATP molecules to complete a folding of a protein.
  4. Jun 23, 2008 #3
    Sure, but I'm really talking about those (many) proteins that don't seem to require chaperones.

    Also, I'll just modify what I first wrote -- the nature of the barrier probably varies from protein to protein, but I still think that it's usually an entropy-dominated effect. The conformational entropy of the protein is lost more quickly than enthalpic gains (enthalpy losses) are made, up to the transition state...
  5. Jun 23, 2008 #4
    Disclaimer: I do not work in the area of protein folding. I do not keep up with the literature on the latest experiments and simulations. I've ended up in the midst of some heated discussions about this field, which I thought were vaguely silly, that I would rather have not been involved in as they were a waste of perfectly good oxygen.

    I want to make sure that I'm understanding you correctly. You want to know how a thermodynamically favorable process (a protein folding to its native state) occurs despite an activation barrier. In this case, welcome to the club. Everyone (metaphorically) wants to understand how protein folding works and its mechanisms and kinetics. Sadly, completely general answers applicable to every possibility will have to wait. I wouldn't hold my breath though.

    I did manage to dig up a review I remember reading on the topic (it's not quite a decade old now). Some choice quotes.....

    -- Alan Cooper (1999) "Thermodynamics of Protein Folding and Stability." Protein: A Comprehensive Treatise Volume 2, pp. 217 - 270. Series Editor: Geoffrey Allen. Publisher: JAI Press Inc.

    Now, I haven't rigorously gone back through the paper to see how well every point Cooper makes holds up at the current moment (nor am I going to - but I'll be happy to send you an Adobe Acrobat version of the paper if you'd like to do so), but the spirit of these quotes is still dead-on, I'd say.
  6. Jun 24, 2008 #5


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    I'll also repeat Mike's disclaimer that I am not an expert on protein folding. My only qualification is having read a few papers and the following review that I will share with you (Shakhnovich E. Protein Folding Thermodynamics and Dynamics: Where Physics, Chemistry, and Biology Meet. Chem. Rev. 2006 May 10;106(5):1559-1588. doi:10.1021/cr040425u).

    One point that the author makes in the review is that protein folding can be thought of like other disorder-order transitions found in nature: as a phase transition. In many phase transitions (e.g. the formation of ice), the barrier is nucleation, the formation of a minimal fragment of the ordered phase. Following Mike's lead, I'll pull a few quotes from the review:

    (ref 98. Abkevich, V. I.; Gutin, A. M.; Shakhnovich, E. I. Biochemistry 1994, 33, 10026)

    Based on this idea of nucleation, the author proposes to consider protein folding as a phase transition rather than as a "chemical reaction" with a free energy barrier:

    The author concludes the section by writing:
    So, knulp's question is still very much an open question in the field of protein folding.
  7. Jun 24, 2008 #6
    Okay. My question was pretty vaguely stated but I meant it to be pretty general, and I think I've become a little more comfortable with the idea.

    The question was, for the protein folding processes that involve a free energy barrier, how do the proteins get over the energy barrier, if it's unfavorable to do so?

    I guess the thing is that despite the barrier, it's generally really only a matter of time before the protein overcomes the barrier just by virtue of random events -- and the higher the barrier, the longer it generally takes.

    The protein might diffuse into a less probable state of lower entropy, thus increasing its free energy -- or the noncovalent bonds between different parts of the protein might weaken on the whole, giving higher potential energy or enthalpy (and free energy)...

    Thanks for your replies.. I think that some of the thinking has changed a bit since the time those papers you cited were written. Nucleation is now more usually thought of as a process that can start in various different parts of the polypeptide, rather than being something that has to happen in one way (in one region of the polypeptide, for instance). And I don't know what the concensus view on protein folding theory prospects might be, but I think Anfinsen sounded overly and unreasonably pessimistic (only after solving n-1 proteins experimentally can we predict the structure of the nth protein, with n being the total number of proteins in the universe? He might have been a pioneer, but come on!).
  8. Jun 25, 2008 #7
    In the review by Shakhnovich that Ygggdrasil quoted, Shakhnovich mentions at the end of the paper:

    I take the opinion that the above is a pretty reasonable answer - while you might be prepare a set of all possible mechanistic elements that are responsible for protein folding, the mix of elements and each one's contribution to the process for that particular protein or protein family is going to vary.

    Even for something that is modeled as a two-state (or nearly so) equilibrium process, the kinetics don't have to be that simple. So having multiple contributions crop up as the protein folds makes a certain intuitive sense in that regard, such that it just doesn't have to be one factor. The possibility that the internal environment of the cell might also be a factor, from viscosity effects to its heterogeneity. I've skimmed across mentions of where dewetting can, in principle, be a major contribution to facilitating folding processes as well (don't have the citation on me, but I think it was in PNAS last year).

    So, for example, if someone told me that protein A had a hydrophobic collapse at one end of the polypeptide chain that served as a nucleation site for the rest of the protein, and spontaneous formation of secondary structure elsewhere that collided where dewetting then occurred, followed by formation of a disulfide bridge which restricted a mobile linker region which initiated the collided secondary structure to wrap around the nucleation site.....it sounds perfectly reasonable. Maybe not as straightforward as some may like, but such it goes.

    I actually thought that sentiment of Anfinsen's was both funny and true. After all, there's a vague sense that we can usually trust macromolecular structures (after all, it's our quantitatively and physics-inclined colleagues doing crystallography and NMR doing that work) as the "native" structure. When you hear about NMR spectroscopists playing fast and loose with the sample conditions so as to minimize linewidth (without much concern about its reasonableness as a faux-biological environment) and how crystal structures are frequently done under cryogenic conditions......well, anyway.

    (FYI, I'm an NMR type who has fiddled around with crystallography. Some honest self-reflection never hurt anyone, I figure.....)
    Last edited: Jun 25, 2008
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