A parsimonious, unifying, minimal model of the HDV ribozyme folding free-energy landscape focused on the catalytic reaction coordinate, indicating the divergence of the trans-acting, cis-acting, and U-1G mutant ribozymes. Below each of the main on-pathway intermediates, structural models as derived from the available crystal structures are depicted. The cis-acting precursor crystal structure (Ke et al. 2004) resembles most closely an early intermediate dominant at physiological pH (left). This intermediate still needs to undergo a conformational change that positions the C75H+ for general acid catalysis and was trapped at low pH in the trans-acting precursor structure (Chen et al. 2010) (middle). If a magnesium hydroxide is bound to the active site simultaneously, cleavage into the product leads to loss of the 5′-precursor sequence and magnesium ion (right).
