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

Abstract

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 β-trefoil structural family members IL-1β, hisactophilin, and acidic/basic FGFs were chosen to address this question. It has been observed that the topological landscape of the β-trefoils allows for the population of diverse, geometrically disconnected routes that provide energetically similar but structurally distinct ways for this family to fold. Small changes in topology or energetics can alter the preferred route. Taken together, these results indicate that the global fold of the β-trefoil family determines the energy landscape but that the routes accessed on that landscape might differ as a result of functional requirements of the individual family members.