Figure 4.

(Lower) Simplified energy diagrams for true two-state folding via nucleation-condensation and apparent two-state kinetics for a framework mechanism that involves the formation of, say, an α-helix, at a higher energy than the denatured state. If both mechanisms involve an extended network of long-range native-like tertiary interactions around the helix, then the free energy of activation, ΔG^‡, responds to changes in structure in a similar manner for both mechanisms, because ΔG^‡ depends just on the difference in energy between similar transition states and the denatured state. (Upper) Two-dimensional representation of the merging of the nucleation-condensation and framework mechanisms. In the framework mechanism, the Φ-values for the formation of the helix are close to 1, because it is relatively stable and can form to an appreciable extent in the absence of tertiary interactions. As the helix becomes less stable, it requires more tertiary interactions to become stable in the transition state, and so the formation of helix is coupled with that of tertiary structure. The Φ-values for formation of the helix can then be appreciably less than 1.