title: Improved prediction of RNA secondary structure by integrating the free energy model with restraints derived from experimental probing data.
abstract: Recently, several experimental techniques have emerged for probing RNA structures based on high-throughput sequencing. However, most secondary structure prediction tools that incorporate probing data are designed and optimized for particular types of experiments. For example, RNAstructure-Fold is optimized for SHAPE data, while SeqFold is optimized for PARS data. Here, we report a new RNA secondary structure prediction method, restrained MaxExpect (RME), which can incorporate multiple types of experimental probing data and is based on a free energy model and an MEA (maximizing expected accuracy) algorithm. We first demonstrated that RME substantially improved secondary structure prediction with perfect restraints (base pair information of known structures). Next, we collected structure-probing data from diverse experiments (e.g. SHAPE, PARS and DMS-seq) and transformed them into a unified set of pairing probabilities with a posterior probabilistic model. By using the probability scores as restraints in RME, we compared its secondary structure prediction performance with two other well-known tools, RNAstructure-Fold (based on a free energy minimization algorithm) and SeqFold (based on a sampling algorithm). For SHAPE data, RME and RNAstructure-Fold performed better than SeqFold, because they markedly altered the energy model with the experimental restraints. For high-throughput data (e.g. PARS and DMS-seq) with lower probing efficiency, the secondary structure prediction performances of the tested tools were comparable, with performance improvements for only a portion of the tested RNAs. However, when the effects of tertiary structure and protein interactions were removed, RME showed the highest prediction accuracy in the DMS-accessible regions by incorporating in vivo DMS-seq data.
authors.affiliation: MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, Center for Plant Biology and Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wu
authors.affiliation: MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, Center for Plant Biology and Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Binbin
authors.initials: B
authors.lastname: Shi
authors.affiliation: MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, Center for Plant Biology and Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Xinqiang
authors.initials: X
authors.lastname: Ding
authors.affiliation: MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, Center for Plant Biology and Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Computer Science and Engineering, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.
authors.forename: Xihao
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Computer Science and Engineering, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.
authors.forename: Kevin Y
authors.initials: KY
authors.lastname: Yip
authors.affiliation: School of Biosciences, University of Exeter, UK Exeter EX4 4QD, UK.
authors.forename: Zheng Rong
authors.initials: ZR
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Biophysics and Center for RNA Biology, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Mathews
authors.affiliation: MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, Center for Plant Biology and Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China zhilu@tsinghua.edu.cn.
authors.forename: Zhi John
authors.initials: ZJ
authors.lastname: Lu
mesh_terms: D000465:Algorithms; D008956:Models, Chemical; D015233:Models, Statistical; D015336:Molecular Probe Techniques; D009690:Nucleic Acid Conformation; D012313:RNA / Q000737:chemistry*; D012984:Software; D013816:Thermodynamics
chemical_list: D012313:RNA