Framework protein folding

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. 

The use of the term ab initio in the context of protein folding should not be confused with its use to describe ab initio quantum chemistry calculations. In both cases, ab initio is meant to convey the idea of from first principles, but die starting point and theoretical framework are different for each. 

Kuwajima K., Yamaya H., Miwa S., Sugai S. and Nagamura T. Rapid formation of secondary structure framework in protein folding studied by stopped-flow circular dichro-ism. FEBS Lett. (1987) 221(1) 115-118. 

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 ... 

The lessons we have learned from physics are of a different nature. The history of physics is replete with examples of the elucidation of connections between what seem to be distinct phenomena and the development of a unifying framework, which, in turn, leads to new observable consequences [13]. Indeed, strong evidence suggests that globular proteins share many common characteristics their ability to fold rapidly and reproducibly in order to create a hydrophobic core, the fact that there seem to be a relatively small number (on the order of a few thousand) of distinct modular folds made up of helices and almost planar sheets, the fact that protein folds are flexible and versatile in order to accomplish the dizzying array of functionalities that these proteins perform, and the unfortunate tendency of proteins to aggregate and form amyloids, which are implicated in human diseases. 

Protein folding. Exploring large conformational transitions is one of several areas where the advantages of implicit solvent framework, and the GB model in particular, become apparent. Several all-atom MD simulations of ah initio folding of small proteins have been reported. Examples include 20-residue "trpcage" protein [40],... 

Framework model The protein folding begins with the secondary structures. This is followed by docking of the pre-formed secondary structure units to produce the native, folded macromolecule (Kim and Baldwin, 1990). For small proteins with stable secondary structure(s), they tend to adopt a-helical and turn or P-hairpin structures. These structures may start the folding process. 

The CAZy classification scheme complements the EC system by providing a protein sequence based framework within which the tremendous wealth of biochemical, mechanistic, and structural information on these enzymes can be united. In particular, the CAZy classification highlights evolutionary relationships between CAZymes, which in turn allow structural and functional relationships to be delineated within and between families. For example, although structural representatives exist for nearly three fourths of the more than 110 GH families, these consist of comparatively few three-dimensional fold types (13,29,30). In turn, catalytic activity can be related to enzyme structure within CAZy Whereas EC 3.2.1.21 describes all enzymes which have converged to become yS-glucosidases, the CAZy database highlights that this activity has been found in enzymes from three separate Families (GHl, GH3, and GH9), each with distinct three-dimensional protein folds employing one of two different catalytic mechanisms (29). 

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 key feature of the framework and nucleation-condensation models is the formation of secondary structure—which might or might not be coupled to the formation of tertiary structure—early in the folding process. It follows that a full description of the mechanism of protein folding also requires an understanding of the rules that stabilize molecular interactions in polypeptides. We consider these rules in Chapter 11. 

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