Figure 6.

Free energy as a function of T and reaction coordinate (e.g., protein compactness). At T₀, the cold denatured state D_C is most stable; at T₄, the heat denatured state. At T₂ the native state is most stable and at T₁ or T₃ the equilibrium constant is approximately 1. F is separated from D_C and D_H by barriers that always lead to cooperative temperature titrations (thick line shows average value of q during titration). A sudden small T-jump from T₀ to T₁ leaves q constant and the protein in the D well, followed by type 1 activated exponential kinetics (left Inset plot). A larger jump from T₀ to T₂ leaves the protein closer to the transition state or on a purely downhill type 0 surface if the free energy bias from D to F is too steep (middle Inset plot); the protein folds nonexponentially downhill. A jump from T₀ to T₃ would presumably result in activated kinetics again because of the onset of heat denaturation.