Unifying evolutionary and thermodynamic information for RNA folding of multiple alignments

Seemann, Stefan E.; Gorodkin, Jan; Backofen, Rolf

The advantage of energy minimization is that it relies on experimentally determined parameters. On the other hand, it is known that methods such as RNAfold (1) and Mfold (2) achieve an overall sensitivity of about 70% (3). For example, H/ACA snoRNAs usually do not produce the characteristic two-stem when the energy minimization alone is used to determine the structure. Instead, information on the functional sites have to be used as additional constraints to the thermodynamic folding (4) (5) (6) . In general, there are several reasons for the inaccuracy of energy minimization. First, the energy model is incomplete, especially for multi-loop structures. Second, there can be alternative structures with similar free energies. And third, true structures are often stabilized by bound molecules. The only feasible way to determine the effects of these inaccuracies is to include phylogenetic information by looking for conserved substructures that cannot be accounted for by thermodynamic folding alone.