Protein folding native folded state

MES)==10 These results suggest tliat C(MES) grows (in all likelihood) only as In N with N. Thus tlie restriction of compactness and low energy of tlie native states may impose an upper bound on tlie number of distinct protein folds. 

Sali A, E Shakhnovich and M Karplus 1994b. PCinetics of Protein Folding. A Lattice Model Study of Requirements for Folding to the Native State, journal of Molecular Biology 235 1614-1636. 

Through combined effects of noncovalent forces, proteins fold into secondary stmctures, and hence a tertiary stmcture that defines the native state or conformation of a protein. The native state is then that three-dimensional arrangement of the polypeptide chain and amino acid side chains that best facihtates the biological activity of a protein, at the same time providing stmctural stabiUty. Through protein engineering subde adjustments in the stmcture of the protein can be made that can dramatically alter its function or stabiUty. 

Measuring Protein Sta.bihty, Protein stabihty is usually measured quantitatively as the difference in free energy between the folded and unfolded states of the protein. These states are most commonly measured using spectroscopic techniques, such as circular dichroic spectroscopy, fluorescence (generally tryptophan fluorescence) spectroscopy, nmr spectroscopy, and absorbance spectroscopy (10). For most monomeric proteins, the two-state model of protein folding can be invoked. This model states that under equihbrium conditions, the vast majority of the protein molecules in a solution exist in either the folded (native) or unfolded (denatured) state. Any kinetic intermediates that might exist on the pathway between folded and unfolded states do not accumulate to any significant extent under equihbrium conditions (39). In other words, under any set of solution conditions, at equihbrium the entire population of protein molecules can be accounted for by the mole fraction of denatured protein, and the mole fraction of native protein,, ie. 

For any given protein, the number of possible conformations that it could adopt is astronomical. Yet each protein folds into a unique stmcture totally deterrnined by its sequence. The basic assumption is that the protein is at a free energy minimum however, calometric studies have shown that a native protein is more stable than its unfolded state by only 20—80 kj/mol (5—20 kcal/mol) (5). This small difference can be accounted for by the favorable... 

A Sail, El Shakhnovich, M Karplus. Kinetics of protein folding A lattice model study of the requirements for folding to the native state. J Mol Biol 235 1614-1636, 1994. 

Figure 6.2 The molten globule state is an important intermediate in the folding pathway when a polypeptide chain converts from an unfolded to a folded state. The molten globule has most of the secondary structure of the native state but it is less compact and the proper packing interactions in the interior of the protein have not been formed.

The collapse of the unfolded state to generate the molten globule embodies the main mystery of protein folding. What is the driving force behind the choice of native tertiary fold from a randomly oriented polypeptide chain ... 

Before protein molecules attain their native folded state they may expose hydrophobic patches to the solvent. Isolated purified proteins will aggregate during folding even at relatively low protein concentrations. Inside cells, where there are high concentrations of many different proteins, aggregation could therefore occur during the folding process. This is prevented by... 

Christian Anfmsen s experiments demonstrated that proteins can fold reversibly. A corollary result of Anfmsen s work is that the native structures of at least some globular proteins are thermodynamically stable states. But the matter of how a given protein achieves such a stable state is a complex one. Cyrus Levinthal pointed out in 1968 that so many conformations are possible for a typical protein that the protein does not have sufficient time to reach its most stable conformational state by sampling all the possible conformations. This argument, termed Levinthal s paradox, goes as follows consider a protein of 100 amino acids. Assume that there are only two conformational possibilities per amino acid, or = 1.27 X 10 ° possibilities. Allow 10 sec for... 

This simple three-state model of protein folding, shown schematically in Figure 7, ascribes a separate force to shaping the structure of each state. Local steric interactions trap the protein chain in a large ensemble of conformations with the correct topology hydrophobic interactions drive the chain to a smaller, more compact subset of conformations then dispersion forces supply the enthalpy loss required to achieve a relatively fixed and rigid ensemble of native conformations. 

As was previously established, the spatial structure of the receptor domains is altered by interaction with the hormone, with DNA, with other proteins, and by the state of the receptor phosphorylation. Different states of folding suppose that the receptor exhibits different surfaces that permit it to gain or to lose affinity for DNA sequences or for proteins, as they are components of the native receptor or of the transcriptional machinery. The different properties that... 

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