Figure 1

(a) Cartoon of the free energy landscape in two-dimensional constraint space. Each point on the two-dimensional grid defines a macrostate, (N _nt , N _hb ), where the free energy, G(N _nt , N _hb ), is calculated. The green shading is meant to describe the native (lower-right) and unfolded (upper-left) basins within the free energy landscape. (Notice that the axes are decreasing from bottom to top and left to right.) At times it is convenient to express the free energy as a function of a one-dimensional flexibility order parameter, θ(N _nt , N _hb ). Grey dashed lines represent (approximate) fronts of constant global flexibility due to tradeoff between two constraints types. The red line denotes the shortest path crossing a single saddle from the unfolded to folded basins. (b) An example one-dimensional free energy landscape highlights the straddling barrier that must be crossed as the protein transitions between folded and unfolded.