Molten globule folding intermediate

J. L. Cleland and T. W. Randolph, Mechanism of polyethylene glycol interactions with molten globule folding intermediate of bovine carbonic B. J. Biol. Chem. 267 3147-3153 (1992). 

Martin, J., Langer, T., Boteva, R., Schramel, A., Horwich, A. L., and Hard, F. U. (1991). Chaperonin-mediated protein folding at the surface of groEL through a molten globule -like intermediate. Nature 352, 36-42. 

A number of proteins are known to pass through a transient intermediate state, the so-called molten globule state. The precise stmctural features of this state are not known, but appear to be compact, and contain most of the regular stmcture of the folded protein, yet have a large side-chain disorder (9). 

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.

Raschke, T. M., and Marqnsee, S., 1997. The kinetic folding intermediate of ribonnclease H resembles the acid molten globule and partially unfolded molecules detected under native conditions. Nature Structural Biology 4 298-304. 

The studies of RNase Aand cytochrome c (Qi etal., 1998 Sosnick etal., 1997) show that caution is required in interpreting burst phenomena in protein folding. However, they do not require a reinterpretation of the cases in which the molten globule character of the burst-intermediate has been established (Arai and Kuwajima, 2000 Chamberlain and Marqusee, 2000). 

Baldwin, R. L. (1991). Molten globule Specific and non-specific folding intermediates Chemtracts Biochem. Mol. Biol. 2, 379-389. 

The chemical shift dispersion (Table 1) and the temperature dependence of the resonance hne shape provides a qualitative measure of whether the structure is well ordered [2]. However, NMR spectroscopy also provides information relevant to the problem of protein folding in the study of the molten globule states. NMR spectroscopic investigations of molten globules may be more demanding than those of ordered proteins due to spectral overlap arising from poor shift dispersion and to short relaxation times that are due to conformational exchange at intermediate rates on the NMR time scale. 

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 ... 

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