RNA-RNA Interaction

The function of an RNA molecule often depends on its interaction with other RNAs. The following routines therefore allows one to predict structures formed by two RNA molecules upon hybridization.

Concatenating RNA sequences

One approach to co-folding two RNAs consists of concatenating the two sequences and keeping track of the concatenation point in all energy evaluations. Correspondingly, many of the cofold() and co_pf_fold() routines take one sequence string as argument and use the the global variable #cut_point to mark the concatenation point. Note that while the RNAcofold program uses the & character to mark the chain break in its input.

To simplify the implementation the partition function computation is done internally in a null model that does not include the duplex initiation energy, i.e. the entropic penalty for producing a dimer from two monomers). The resulting free energies and pair probabilities are initially relative to that null model. In a second step the free energies can be corrected to include the dimerization penalty, and the pair probabilities can be divided into the conditional pair probabilities given that a re dimer is formed or not formed. See Bernhart et al. [2006] for further details.

As for folding one RNA molecule, this computes the partition function of all possible structures and the base pair probabilities. Uses the same global #pf_scale variable to avoid overflows.

After computing the partition functions of all possible dimers one can compute the probabilities of base pairs, the concentrations out of start concentrations and sofar and soaway.

Dimer formation is inherently concentration dependent. Given the free energies of the monomers A and B and dimers AB, AA, and BB one can compute the equilibrium concentrations, given input concentrations of A and B, see e.g. Dimitrov & Zuker (2004)

RNA-RNA interaction as a Stepwise Process

In this approach to cofolding the interaction between two RNA molecules is seen as a stepwise process. In a first step, the target molecule has to adopt a structure in which a binding site is accessible. In a second step, the ligand molecule will hybridize with a region accessible to an interaction. Consequently the algorithm is designed as a two step process: The first step is the calculation of the probability that a region within the target is unpaired, or equivalently, the calculation of the free energy needed to expose a region. In the second step we compute the free energy of an interaction for every possible binding site.

This approach is implemented for the interaction between a long target sequence and a short ligand RNA. Function pf_unstru() calculates the partition function over all unpaired regions in the input sequence. Function pf_interact(), which calculates the partition function over all possible interactions between two sequences, needs both sequence as separate strings as input.