Kinetic control, of protein folding

R M. Horowitz, Kinetic control of protein folding by detergent micelles, liposomes, and chaperonins. Protein Folding In Vivo and In Vitro (J. L. Cleland, ed.), American Chemical Society Symposium Series Volume 526, 1993, pp. 156-163. 

According to this hypothesis, the native structure represents the most stable structure. On the other hand, the concept of kinetic control of protein folding means that some energetic barrier could hinder the access of the most stable conformation, thus trapping the structure in a metastable state. The idea of kinetic control of protein folding has been defined by Wetlaufer and Ristow (1973) ... 

At this time, thermodynamic and kinetic control of protein folding does not seem mutually exclusive. It might considered a plausible assumption that the native conformation is the one of lowest energy but is reached through kinetically controlled intermediates. 

From these earlier studies, it was thought more or less explicitly that the formation of the tertiary structure of native proteins is a thermodynamically controlled process. The conformational studies which used synthetic polypeptides strongly supported this. As an alternative to the thermodynamic hypothesis, the kinetic control of protein folding appeared when Levinthal (1968a,b) on the basis of time consideration discarded the possibility of a random search of the most stable conformation even for a small protein. Now, these two hypotheses do not appear mutually exclusive the final state can be under thermodynamic control and intermediary steps under kinetic control. 

The experimental data mentioned in this section and in more detail in other reviews, substantiates the general theoretical framework for protein folding and function given by the single funnel hypothesis. However, in spite of all the studies, theoretical and experimental, that seem to support it, there is not, as yet, a definitive proof for the single funnel hypothesis and in the next sections an alternative theoretical framework, based on a kinetic control of folding, will be put forward. 

A thermodynamically stable conformation arises from the minimization of the overall free energy of interaction resulting from all intramolecular and intermolecular contributions. Whatever the control of the folding process may be, thermodynamic or kinetic, the conformation must be thermodynamically stable with respect to small perturbations of the molecular geometry. Of course, it is also stable relatively to the unfolded state. In spite of controversies, the thermodynamic hypothesis represents a necessary working hypothesis for all current attempts of a theoretical analysis of protein stability and for determination of the allowed conformations of a polypeptide chain. 

Baskakov, I. V., Legname, G., Prusiner, S. B., and Cohen, F. E. (2001). Folding of prion protein to its native a-helical conformation is under kinetic control. J. Biol. Chem. 276, 19687-19690. 

Is the folding of proteins activated by chaperons under thermodynamic, or under kinetic, control ... 

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