Figure 3. Examples of diversity amongst protein folding mechanisms.

(A): Most proteins currently used as folding models are marginally stable (black), meaning that their folded lifetime (t_1/2) is short. Lifetime can be increased in two ways. The native structure can be stabilized thermodynamically, increasing the energetic difference between the denatured ensemble and the native structure (increasing ΔG^o_folding, blue). Alternatively, the energetic barrier separating the denatured ensemble and the native conformation (ΔG^‡) can be increased (red); this will preserve the (low) thermodynamic stability but increase the folded state lifetime. Increasing the energy barrier yields kinetically stable proteins, which can be identified by proteome-wide folding screens [42, 43] (see also Figure 1B). (B): Proteins fold from an ensemble of unfolded states, represented by the wide top of a protein folding funnel. In simple model systems (yellow), the funnel has one energy minimum, the native conformation. However, some proteins have a more complex energy landscape and can adopt alternative folded structures (green). These two folded structures may interconvert, or features of the cellular environment may stabilize a subset of early folding intermediates, resulting in a biased accumulation of one structure versus the other(s).