Topology Links RNA Secondary Structure with Global Conformation, Dynamics, and Adaptation

RNA Structural Principles Revealed The thermodynamic principles that link RNA primary and secondary structure are well understood, but the relation to tertiary structure is unclear. To gain insight, Bailor et al. (p. 202) analyzed all available three-dimensional structures of an important RNA motif, the two-way junction, and found that flanking helices sample only a small percentage of possible interhelical orientations. They identified a set of general rules for the relative orientation of helices as a function of the size of the interconnecting junction. The results also rationalize how ligands stabilize specific conformations. Understanding the topological constraints that define RNA global conformation and dynamic adaptation provides guiding principles for rational manipulation of RNA structure. Topological constraints imposed by the secondary structure determine the global conformation ensemble sampled by RNA. Thermodynamic rules that link RNA sequences to secondary structure are well established, but the link between secondary structure and three-dimensional global conformation remains poorly understood. We constructed comprehensive three-dimensional maps depicting the orientation of A-form helices across RNA junctions in the Protein Data Bank and rationalized our findings with modeling and nuclear magnetic resonance spectroscopy. We show that the secondary structures of junctions encode readily computable topological constraints that accurately predict the three-dimensional orientation of helices across all two-way junctions. Our results suggest that RNA global conformation is largely defined by topological constraints encoded at the secondary structural level and that tertiary contacts and intermolecular interactions serve to stabilize specific conformers within the topologically allowed ensemble.