Small angle X-ray scattering reveals a compact intermediate in RNA folding

We have used small angle X-ray scattering (SAXS) to monitor changes in the overall size and shape of the Tetrahymena ribozyme as it folds. The native ribozyme, formed in the presence of Mg2+, is much more compact and globular than the ensemble of unfolded conformations. Time-resolved measurements sh ow that most of the compaction occurs at least 20-fold faster than the over all folding to the native state, suggesting that a compact intermediate or family of intermediates is formed early and then rearranges in the slow ste ps that limit the overall folding rate. These results lead to a kinetic fol ding model in which an initial 'electrostatic collapse' of the RNA is follo wed by slower rearrangements of elements that are initially mispositioned.