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funnel concept

The new view of the protein folding problem in which the assortment of unfolded polypeptides are considered as an ensemble, the myriad of individual members of which achieve the native form by microscopically unique routes, all funneling down from the high-energy unfolded state to the low energy native conformation. If these molecules, on average, do not encounter an obstacle to refolding, the kinetics appears like the two-state case of the pathway model. Obstacles may be dead ends (kinetic traps) from which the miss-folded protein is extracted by Browninan forces or helped by a chaperonin to reverse to a higher energy state from which it can continue its folding. Another kind of bottleneck is a conformational entropy barrier, when there are only small differences in energy among the various possible conformations each folding polymer can achieve. It would then take some time, on the average, for the partially folded molecules to search the many possible conformations to find a continuation of the folding sequence. By viewing the energy co-ordinate as an energy landscape, folding of specific unfolded proteins may be viewed as passing over plateaus, down steep ravines or trapped in moats. Although the funnel concept, or 'new view' of protein folding was proposed as an alternative to the hypothesis that each protein has only one folding pathway (the 'old view), there in fact may be multiple pathways, but they share many features.see framework model; kinetic partitioning; paradox of LevinthalDill, K.A. and Chan, H.S. (1997) Nat. Struct. Biol. 4, 10-19; Lazaridis, T. and Karplus, M (1997) Science 278, 1928-1931; Pande, V.S., Grosberg, A.Yu., Tanaka, T. and Rokhsar, D.S. (1998) Curr. Opin. Struct. Biol. 8, 68-79; Dobson, C.M. and Ellis, R.J. (1998) EMBO J. 17 5251-5254; Dobson, C.M. and Ptitsyn, O.B. (1999) Curr. Opin Struct. Biol. 9, 89-91; Baker, D. (2000) Nature (London) 405, 39-42; Honig B.F (1999) J. Mol. Biol. 293, 283-293; and Accts. Chem. Res. 31, 697-780 (special issue on protein folding)

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