Multiple routes lead to the native state in the energy landscape of the beta-trefoil family.

In general, the energy landscapes of real proteins are sufficiently well designed that the depths of local energetic minima are small compared with the global bias of the native state. Because of the funneled nature of energy landscapes, models that lack energetic frustration have been able to capture the main structural features of the transition states and intermediates found in experimental studies of both small and large proteins. In this study we ask: Are the experimental differences in folding mechanisms among members of a particular structural family due to local topological constraints that deviate from the tertiary fold common to the family? The beta-trefoil structural family members IL-1beta, hisactophilin, and acidic/basic FGFs were chosen to address this question.