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      Integration of accessibility data from structure probing into RNA–RNA interaction prediction

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          Abstract

          Summary

          Experimental structure probing data has been shown to improve thermodynamics-based RNA secondary structure prediction. To this end, chemical reactivity information (as provided e.g. by SHAPE) is incorporated, which encodes whether or not individual nucleotides are involved in intra-molecular structure. Since inter-molecular RNA–RNA interactions are often confined to unpaired RNA regions, SHAPE data is even more promising to improve interaction prediction. Here, we show how such experimental data can be incorporated seamlessly into accessibility-based RNA–RNA interaction prediction approaches, as implemented in IntaRNA. This is possible via the computation and use of unpaired probabilities that incorporate the structure probing information. We show that experimental SHAPE data can significantly improve RNA–RNA interaction prediction. We evaluate our approach by investigating interactions of a spliceosomal U1 snRNA transcript with its target splice sites. When SHAPE data is incorporated, known target sites are predicted with increased precision and specificity.

          Availability and implementation

          https://github.com/BackofenLab/IntaRNA

          Supplementary information

          Supplementary data are available at Bioinformatics online.

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          Most cited references14

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          Selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE): quantitative RNA structure analysis at single nucleotide resolution.

          Selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) interrogates local backbone flexibility in RNA at single-nucleotide resolution under diverse solution environments. Flexible RNA nucleotides preferentially sample local conformations that enhance the nucleophilic reactivity of 2'-hydroxyl groups toward electrophiles, such as N-methylisatoic anhydride (NMIA). Modified sites are detected as stops in an optimized primer extension reaction, followed by electrophoretic fragment separation. SHAPE chemistry scores local nucleotide flexibility at all four ribonucleotides in a single experiment and discriminates between base-paired versus unconstrained or flexible residues with a dynamic range of 20-fold or greater. Quantitative SHAPE reactivity information can be used to establish the secondary structure of an RNA, to improve the accuracy of structure prediction algorithms, to monitor structural differences between related RNAs or a single RNA in different states, and to detect ligand binding sites. SHAPE chemistry rarely needs significant optimization and requires two days to complete for an RNA of 100-200 nucleotides.
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            IntaRNA 2.0: enhanced and customizable prediction of RNA–RNA interactions

            Abstract The IntaRNA algorithm enables fast and accurate prediction of RNA–RNA hybrids by incorporating seed constraints and interaction site accessibility. Here, we introduce IntaRNAv2, which enables enhanced parameterization as well as fully customizable control over the prediction modes and output formats. Based on up to date benchmark data, the enhanced predictive quality is shown and further improvements due to more restrictive seed constraints are highlighted. The extended web interface provides visualizations of the new minimal energy profiles for RNA–RNA interactions. These allow a detailed investigation of interaction alternatives and can reveal potential interaction site multiplicity. IntaRNAv2 is freely available (source and binary), and distributed via the conda package manager. Furthermore, it has been included into the Galaxy workflow framework and its already established web interface enables ad hoc usage.
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              Thermodynamics of RNA-RNA binding.

              Reliable prediction of RNA-RNA binding energies is crucial, e.g. for the understanding on RNAi, microRNA-mRNA binding and antisense interactions. The thermodynamics of such RNA-RNA interactions can be understood as the sum of two energy contributions: (1) the energy necessary to 'open' the binding site and (2) the energy gained from hybridization. We present an extension of the standard partition function approach to RNA secondary structures that computes the probabilities Pu[i, j] that a sequence interval [i, j] is unpaired. Comparison with experimental data shows that Pu[i, j] can be applied as a significant determinant of local target site accessibility for RNA interference (RNAi). Furthermore, these quantities can be used to rigorously determine binding free energies of short oligomers to large mRNA targets. The resource consumption is comparable with a single partition function computation for the large target molecule. We can show that RNAi efficiency correlates well with the binding energies of siRNAs to their respective mRNA target. RNAup will be distributed as part of the Vienna RNA Package, www.tbi.univie.ac.at/~ivo/RNA/
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                Author and article information

                Contributors
                Role: Associate Editor
                Journal
                Bioinformatics
                Bioinformatics
                bioinformatics
                Bioinformatics
                Oxford University Press
                1367-4803
                1367-4811
                15 August 2019
                27 December 2018
                27 December 2018
                : 35
                : 16
                : 2862-2864
                Affiliations
                [bty1029-aff1 ]Department of Computer Science, Bioinformatics Group, University of Freiburg, Freiburg D-79110, Germany
                [bty1029-aff2 ]Center for Biological Signaling Studies (BIOSS), University of Freiburg, Freiburg D-79104, Germany
                Author notes
                Author information
                http://orcid.org/0000-0002-0173-3009
                http://orcid.org/0000-0002-7926-5911
                Article
                bty1029
                10.1093/bioinformatics/bty1029
                6691327
                30590479
                e72f097a-571f-4bdf-aa39-df46df33418a
                © The Author(s) 2018. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 12 July 2018
                : 20 November 2018
                : 18 December 2018
                Page count
                Pages: 3
                Funding
                Funded by: Bundesministerium für Bildung und Forschung 10.13039/501100002347
                Award ID: 031A538A RBC
                Award ID: 031L0106B
                Funded by: Deutsche Forschungsgemeinschaft 10.13039/501100001659
                Award ID: BA 2168/14-1
                Award ID: BA 2168/16-1
                Categories
                Applications Notes
                Structural Bioinformatics

                Bioinformatics & Computational biology
                Bioinformatics & Computational biology

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