Downhill Folding - Overview

Overview

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.