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The concept of a free energy (FE) landscape, in which the conformations of a polymer progressively take on the structure of the native state while spiraling down a FE surface that resembles the shape of a funnel, has long been viewed as the reason why a complex protein structure forms so rapidly compared to the number of conformations available to it. On the other hand, this landscape picture is less clear with RNA due to the multiplicity of conformations and the uncertainties in the current thermodynamics. It is therefore sometimes proposed that within the ensemble of suboptimal states of the RNA molecule, the vast majority of those states all closely resemble the native state and therefore simply overwhelm the few states that represent the global minimum FE. However, calculations of the free energy of observed structures often suggest that the most frequently observed cluster of structures are far from the minimum FE, particularly in the case of long sequences. If so, then such a FE surface is unlikely to be funnel shaped. We have been developing a version of vsfold that can evaluate the suboptimal structures of the FE surface (through a modified version called vs_subopt ). Here we show that the ensemble of suboptimal structures for a number of known RNA structures can actually be both close to the minimum FE and also be the dominant observed structure when a proper Kuhn length is selected. Two state aptamers known as riboswitches can show neighboring FE states in the suboptimal structures that match the observed structures and their relative difference in FE is well within the range of the binding free energy of the metabolite. For the riboswitches and other short RNA sequences (less than 250 nt), the flow of the suboptimal structures (including pseudoknots) tended to resemble a rock rolling down a hill along the reaction coordinate axis. An important insight yielded by the cross-linking entropy (CLE) model is that the global entropy limits the size of domains. Hence, based on the CLE model, Levinthal’s paradox is overcome by the funnel shape in the FE, by a reduction in the number of degrees of freedom due to Kuhn length, and by limits on the size of the domains that can form. These concepts are also applicable to calculating transition rates between different suboptimal structures.

A new entropy model for RNA: part III. Is the folding free energy landscape of RNA funnel shaped?