Investigating the concept of accessibility for predicting novel RNA-RNA interactions

State-of-the-art methods for predicting novel trans RNA-RNA interactions use the so-called accessibility as key concept. It estimates whether a region in a given RNA sequence is accessible for forming trans interactions, using a thermodynamic model which quantifies its secondary structure features. RNA-RNA interactions are then predicted by finding the minimum free energy base-pairing between the two transcripts, taking into account the accessibility as energy penalty. We investigated the underlying assumptions of this approach using the two methods RNAO_SCPLOWPLEXC_SCPLOW and IO_SCPLOWNTAC_SCPLOWRNA on two datasets, containing sRNA-mRNA and snoRNA-rRNA interactions, respectively. We find that (1) known trans RNA-RNA interactions frequently overlap regions containing RNA structure features, (2) the estimated accessibility reflects sRNA structures fairly well, but often disagrees with structure annotations of longer transcripts, (3) the prediction performance of RNA-RNA interaction prediction methods is independent of the quality of the estimated accessibility profiles, and (4) one important overall effect of accessibility profiles is to prevent the thermodynamic model from predicting too long interactions. Based on our findings, we conclude that the accessibility concept to the minimum free energy approach to predicting novel RNA-RNA interactions has conceptual limitations and discuss potential ways of improving the field in the future.