Bamase, folding intermediates

The structure of a compact state on the folding pathway of bamase has been mapped out in detail at the level of individual residues and is discussed in detail later (Chapter 19) using the value analysis of the next section.32 Its structure is clearly between that of the unfolded state and the major transition state for folding. It has the same elements of secondary structure and the same tertiary contacts, but they are all weaker, especially in the hydrophobic core. The structure has all the properties expected of a folding intermediate that is on the pathway and has no indications of alternative structure. This does not prove that it is on the pathway, but the most likely explanation is that it is. 

The two situations above do occur for many mutations in bamase. We can simply go around the structure checking fully native or fully denatured at the relevant regions and so get a detailed residue-by-residue characterization of its folding intermediate and transition state. Each mutation is a reporter group for what is happening at the site of mutation during the folding pathway. 

Dalby, P.A., Clarke, J., Johnson, C.M., Fersht, A.R. (1998) Folding intermediates of wild-type and mutants of bamase. 11. Correlation of changes in equilibrium amide exchange kinetics with the population of the folding intermediate. Journal of Molecular Biology, 276 (3), 647-656. 

N. D. Socci, Z. Luthey Schulten, and P. G. Wolynes, Folding and Design 1,441 (1996).] Bottom Structures of the denatured, intermediate, major transition, and native states for folding of bamase from molecular dynamics simulations that were benchmarked by < > values and NMR experiments. [Data from C. J. Bond, K. B. Wong, J. Clarke,... 

The third test is deviations from the simple V-shaped curves of rate constants versus [denaturant] that were shown in Figure 18.1 for CI2. An intermediate was detected from the denaturant dependence of the single phase for the folding of bamase (Figure 18.6) because of downward curvature. This is sometimes called rollover. The rate constant for folding for the two-state transition for bamase can be calculated as a function of [urea] from the equilibrium and rate constants... 

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