Downhill folding

Downhill folding is a process in which a protein folds without encountering any significant macroscopic free energy barrier. It is a key prediction of the folding funnel hypothesis of the energy landscape theory of proteins.

Downhill folding is predicted to occur under conditions of extreme native bias, i.e. at low temperatures or in the absence of denaturants. This corresponds to the type 0 scenario in the energy landscape theory. At temperatures or denaturant concentrations close to their apparent midpoints, proteins may switch from downhill to two-state folding, the type 0 to type 1 transition.

Global downhill folding (or one-state folding) is another scenario in which the protein folds in the absence of a free energy barrier under all conditions. In other words, there is a unimodal population distribution at all temperatures and denaturant concentrations, suggesting a continuous unfolding transition in which different ensembles of structures populate at different conditions. This is in contrast to two-state folding, which assumes only two ensembles (folded and unfolded) and a sharp unfolding transition.

Free energy barriers in protein folding are predicted to be small because they arise as a result of compensation between large energetic and entropic terms. Non-synchronization between gain in stabilizing energy and loss in conformational entropy results in two-state folding, while a synchronization between these two terms as the folding proceeds results in downhill folding.

Transition state structures in two-state folding are not experimentally accessible (by definition they are the least populated along the reaction coordinate), but the folding sub-ensembles in downhill folding processes are theoretically distinguishable by spectroscopy. The 40-residue protein BBL, which is an independently folding domain from the E2 subunit of the 2-oxoglutarate dehydrogenase multi-enzyme complex of E. coli, has been experimentally shown to fold globally downhill. Also, a mutant of lambda repressor protein has been shown to shift from downhill to two-state upon changing the temperature/solvent conditions. However, the status of BBL as a downhill-folding protein, and by extension the existence of naturally occurring downhill folders, has been controversial. The current controversy arises from the fact that the only way a protein can be labeled as two-state or downhill is by analyzing the experimental data with models that explicitly deal with these two situations, i.e. by allowing the barrier heights to vary. Unfortunately, most of the experimental data so far have been analyzed with a simple chemical two-state model. In other words, the presence of a rather large free energy barrier has been pre-assumed, ruling out the possibility of identifying downhill or globally downhill protein folding. This is critical because any sigmoidal unfolding curve, irrespective of the degree of cooperativity, can be fit to a two-state model. Kinetically, the presence of a barrier guarantees a single-exponential, but not vice versa. Nevertheless, in some proteins such as the yeast phosphoglycerate kinase and a mutant human ubiquitin, non-exponential kinetics suggesting downhill folding have been observed.

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