Using a statistical mechanical treatment, we study RNA folding energy landscapes. We first validate the theory by showing that, for the RNA molecules we tested having only secondary structures, this treatment (I) predicts about the same native structures as the Zuker method. and (ii) qualitatively predicts the melting curve peaks and shoulders seen in experiments. We then predict ther- modynamic folding intermediates. For one hairpin sequence. un- folding is a simple unzipping process. But for another sequence, unfolding is more complex. It involves multiple stable intermedi- ates and a rezipping into a completely non-native con formation before unfolding. The principle that emerges, for which there is growing experimental support, is that although protein folding tends to involve highly cooperative two-state thermodynamic transitions, without detectable intermediates, the folding of RNA secondary structures may involve rugged landscapes, often with more complex intermediate states.
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