Structural specificity conferred by a group I RNA peripheral element

Like proteins, structured RNAs must specify a native conformation that is more stable than all other possible conformations. Local structure is much more stable for RNA than for protein, so it is likely that the principal challenge for RNA is to stabilize the native structure relative to misfolded and partially folded intermediates rather than unfolded structures. Many structured RNAs contain peripheral structural elements, which surround the core elements. Although it is clear that peripheral elements stabilize structure within RNAs that contain them, it has not yet been explored whether they specifically stabilize the native states relative to alternative folds. A two-piece version of the group I intron RNA from Tetrahymena is used here to show that the peripheral element P5abc binds to the native conformation of the rest of the RNA 50,000 times more tightly than it binds to a long-lived misfolded conformation. Thus, P5abc stabilizes the native conformation by approximate to 6 kcal/mol relative to this misfolded conformation. Further, activity measurements show that for the RNA lacking P5abc, the native conformation is only marginally preferred over the misfolded conformation (< 0.5 kcal/mol), indicating that the peripheral structure of this RNA is required to achieve a significant thermodynamic preference for the native state. Such "structural specificity" may be a general function of RNA peripheral domains.