A basic limitation of this approach arises from the no-pseudoknots condition: It restricts not only the intramolecular base pairs but also affects intermolecular pairs. Let SA and SB denote the intramolecular pairs in a cofolded structure S. These sets of base pairs define secondary structures on A and B respectively. Because of the no-pseudoknot condition on S, an intermolecular base pair in S\(SA ∪ SB) can only connect nucleotides in the external loops of A and B. This is a serious restriction for some applications, because it excludes among other pseudoknot-like structures also the so-called kissing hairpin complexes [46]. Taking such structures into account is equivalent to employing folding algorithms for structure models that include certain types of pseudoknots, such as the partition function approach by Dirks and Pierce [40]. Its high computational cost, however, precludes the analysis of large mRNAs. In an alternative model [29], no intramolecular interactions are allowed in the small partner B, thus allowing B to form basepairs with all contiguous unpaired regions in SA. From a biophysical point of view, however, it makes sense to consider exclusively hybridization in the exterior loop provided both partners are large structured RNAs. In this case, hybridization either stops early, i.e., at a kissing hairpin complex (in the case of very stable local structures) or it is thermodynamically controlled and runs into the ground state via a complete melting of the local structure. In the latter case, the no-pseudoknots condition is the same approximation that is also made when folding individual molecules. Note that this approximation does not imply that the process of hybridization could only start at external bases.