Maximizing RNA folding rates: A balancing act

Large ribozymes typically require very long times to refold into their acti ve conformation in vitro, because the RNA is easily trapped in metastable m isfolded structures. Theoretical models show that the probability of misfol ding is reduced when local and long-range interactions in the RNA are balan ced. Using the folding kinetics of the Tetrahymena ribozyme as an example, we propose that folding rates are maximized when the free energies of formi ng independent domains are similar to each other. A prediction is that the folding pathway of the ribozyme can be reversed by inverting the relative s tability of the tertiary domains. This result suggests strategies for optim izing ribozyme sequences for therapeutics and structural studies.