Thermodynamics protein folding/unfolding

Equations (l)-(4) provide the basic statistical thermodynamic framework necessary to deal with the protein folding problem. Several years ago, Freire and Biltonen (1978a) showed that scanning calorimetry data could be used to evaluate the protein folding/unfolding partition function experimentally by a double integration procedure ... 

An interesting aspect of the photoreaction of PYP is the similarity to the protein folding/unfolding reaction. Hellingwerf and his coworkers applied the transition state theory to the photoreaction of PYP and estimated the thermodynamic parameters, the entropy, enthalpy, and heat capacity changes of activation [29]. They also carried out thermodynamic analysis on the thermal denaturation of PYP. Consequently, they found that the heat capacity changes in the photoreaction are comparable to those in the unfolding... 

Freire E. Statistical thermodynamic analysis of (he heat capacity function associated with protein folding-unfolding transitions. Coimnents Mol Cell Biophys 1989 6(2) 123-140. 

We present a molecular theory of hydration that now makes possible a unification of these diverse views of the role of water in protein stabilization. The central element in our development is the potential distribution theorem. We discuss both its physical basis and statistical thermodynamic framework with applications to protein solution thermodynamics and protein folding in mind. To this end, we also derive an extension of the potential distribution theorem, the quasi-chemical theory, and propose its implementation to the hydration of folded and unfolded proteins. Our perspective and current optimism are justified by the understanding we have gained from successful applications of the potential distribution theorem to the hydration of simple solutes. A few examples are given to illustrate this point. 

Daura, X., van Gunsteren, W. F., and Mark, A. E. (1999b). Folding-unfolding thermodynamics of a /3-heptapeptide from equilibrium simulations. Proteins Strud. Fund. 

A puzzling problem was posed by Levinthal many years ago.329 We usually assume that the peptide chain folds into one of the most stable conformations possible. However, proteins fold very rapidly. Even today, no computer would be able, in our lifetime, to find by systematic examination the thermodynamically most stable conformation.328 It would likewise be impossible for a folding protein to "try out" more than a tiny fraction of all possible conformations. Yet folded and unfolded proteins often appear to be in a thermodynamic equilibrium Experimental results indicate that denatured proteins are frequently in equilibrium with a compact denatured state or "molten globule" in which hydrophobic groups have become clustered and some secondary structures exists.330-336 From this state the polypeptide may rearrange more slowly through other folding intermediates to the final "native conformation."3363 3361 ... 

We cannot answer the question posed by Anfin-sen s hypothesis. Does the native state have a minimum value of the Gibbs energy Nevertheless, it is observed that proteins usually behave as if folded, unfolded forms are in a true thermodynamic equilibrium, and that this equilibrium is attained rapidly. The difference AG between a folded and a denatured protein is only 21-63 kj mol-1, which shows that folded proteins are only marginally more stable than are unfolded polypeptide chains.645 The value of AG of unfolding as a function of temperature T is given by Eq. 29-13, where AH(T) and ACp are the changes in enthalpy and heat capacity upon unfolding.645 646... 

From a statistical thermodynamic standpoint, the description of the folding/unfolding equilibrium in proteins requires the specification of the system partition function, Q defined as the sum of the statistical weights of all the possible states of the molecule (see Freire and Biltonen, 1978a) ... 

It has been shown that under standard conditions most singledomain globular proteins exhibit a folding/unfolding behavior consistent with the two-state mechanism (Freire and Biltonen, 1978a Privalov, 1979). From a statistical thermodynamic standpoint the implication is that the population of partially folded intermediate states is negligible and the partition function reduces to two terms ... 

Directed evolution as a tool to probe the basis of protein structure, stability, and function is in its infancy, and many fruitful avenues of research remain to be explored. Studies so far have focused on proteins that unfold irreversibly, making detailed thermodynamic analysis impossible. The application of these methods to reversibly folding proteins could provide a wealth of information on the thermodynamic basis of high temperature stability. A small number of studies on natural thermophilic proteins have identified various thermodynamic strategies for stabilization. Laboratory evolution makes it possible to ask, for example, whether proteins have adopted these different strategies by chance, or whether certain protein architectures favor specific thermodynamic mechanisms. It will also be possible to determine how other selective pressures, such as the requirement for efficient low temperature activity, influence stabilization mechanisms. The combination of directed evolu-... 

In 1987 [8] and again in 1993 [9], it was pointed out that the hydrophobic liquid model could not be entirely adapted to protein folding, since it completely fails to explain the effects of pressure. Kauzmann points out that volume and enthalpy changes are equally fundamental properties of the unfolding process, and no model can be considered acceptable unless it accounts for the entire thermodynamic behaviour In his Reminiscences from a Life in Protein Physical Chemistry [10], Kauzmann further states ... 

Protein folding and unfolding is thus largely an "all or none"process that results horn a cooperative transition. For example, suppose that a protein is placed in conditions under which some part of the protein structure is thermodynamically unstable. As this part of the folded structure is disrupted, the interactions between it and the remainder of the protein will be lost. The loss of these interactions, in turn, will destabilize the remainder of the structure. Thus, conditions that lead to the disruption of any part of a protein structure are likely to unravel the protein completely. The structural properties of proteins provide a clear rationale for the cooperative transition. 

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