Disparate HDV ribozyme crystal structures represent intermediates on a rugged free-energy landscape

The hepatitis delta virus (HDV) ribozyme is a member of the class of small, self-cleaving catalytic RNAs found in a wide range of genomes from HDV to human. Disparate pre- and post-catalysis (precursor and product) crystal structures have been determined, including a most recent trans-acting precursor resembling a previous product structure. Using fluorescence resonance energy transfer (FRET) assays together with a total of 1.8 µsec of molecular dynamics (MD) simulations, the authors show here that the available crystal structures represent intermediates on an overall rugged RNA folding free-energy landscape, where a conformational change accompanies catalysis of the HDV ribozyme.