New approaches to targeting RNA with oligonucleotides: Inhibition of group I intron self‐splicing

Disney, Matthew D.; Childs, Jessica L.; Turner, Douglas H.

doi:10.1002/bip.10520

Cited by 19 publications

(16 citation statements)

References 98 publications

(108 reference statements)

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“…40−43 Much less effort, however, has been applied to development and testing of force fields for RNA. The emerging recognition that RNA has many different cellular functions 1−6 and that many RNAs are potential therapeutic targets 27,44−47 increases the importance of force fields for RNA.…”

Section: Discussionmentioning

confidence: 99%

Revision of AMBER Torsional Parameters for RNA Improves Free Energy Predictions for Tetramer Duplexes with GC and iGiC Base Pairs

Yildirim

Kennedy

Stern

et al. 2011

J. Chem. Theory Comput.

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161

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All-atom force fields are important for predicting thermodynamic, structural, and dynamic properties of RNA. In this paper, results are reported for thermodynamic integration calculations of free energy differences of duplex formation when CG pairs in the RNA duplexes r(CCGG)2, r(GGCC)2, r(GCGC)2, and r(CGCG)2 are replaced by isocytidine–isoguanosine (iCiG) pairs. Agreement with experiment was improved when ε/ζ, α/γ, β, and χ torsional parameters in the AMBER99 force field were revised on the basis of quantum mechanical calculations. The revised force field, AMBER99TOR, brings free energy difference predictions to within 1.3, 1.4, 2.3, and 2.6 kcal/mol at 300 K, respectively, compared to experimental results for the thermodynamic cycles of CCGG → iCiCiGiG, GGCC → iGiGiCiC, GCGC → iGiCiGiC, and CGCG → iCiGiCiG. In contrast, unmodified AMBER99 predictions for GGCC → iGiGiCiC and GCGC → iGiCiGiC differ from experiment by 11.7 and 12.6 kcal/mol, respectively. In order to test the dynamic stability of the above duplexes with AMBER99TOR, four individual 50 ns molecular dynamics (MD) simulations in explicit solvent were run. All except r(CCGG)2 retained A-form conformation for ≥82% of the time. This is consistent with NMR spectra of r(iGiGiCiC)2, which reveal an A-form conformation. In MD simulations, r(CCGG)2 retained A-form conformation 52% of the time, suggesting that its terminal base pairs may fray. The results indicate that revised backbone parameters improve predictions of RNA properties and that comparisons to measured sequence dependent thermodynamics provide useful benchmarks for testing force fields and computational methods.

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Section: Discussionmentioning

confidence: 99%

Revision of AMBER Torsional Parameters for RNA Improves Free Energy Predictions for Tetramer Duplexes with GC and iGiC Base Pairs

Yildirim

Kennedy

Stern

et al. 2011

J. Chem. Theory Comput.

Self Cite

161

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“…RNA structural motifs may be targeted with oligonucleotides (Childs et al 2002(Childs et al , 2003Disney et al 2004) or small molecules (Mei et al 1998;Sucheck and Wong 2000;Wilson and Li 2000;Gallego and Varani 2001;Childs-Disney et al 2007;Disney et al 2008; Lee et al 2009;Pushechnikov et al 2009) to disrupt viral function.…”

Section: Introductionmentioning

confidence: 99%

Identification of potential conserved RNA secondary structure throughout influenza A coding regions

Moss¹,

Priore²,

Turner³

2011

RNA

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163

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Influenza A is a negative sense RNA virus of significant public health concern. While much is understood about the life cycle of the virus, knowledge of RNA secondary structure in influenza A virus is sparse. Predictions of RNA secondary structure can focus experimental efforts. The present study analyzes coding regions of the eight viral genome segments in both the (+) and (-) sense RNA for conserved secondary structure. The predictions are based on identifying regions of unusual thermodynamic stabilities and are correlated with studies of suppression of synonymous codon usage (SSCU). The results indicate that secondary structure is favored in the (+) sense influenza RNA. Twenty regions with putative conserved RNA structure have been identified, including two previously described structured regions. Of these predictions, eight have high thermodynamic stability and SSCU, with five of these corresponding to current annotations (e.g., splice sites), while the remaining 12 are predicted by the thermodynamics alone. Secondary structures with high conservation of base-pairing are proposed within the five regions having known function. A combination of thermodynamics, amino acid and nucleotide sequence comparisons along with SSCU was essential for revealing potential secondary structures.

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“…Group I and group II introns have also been engineered as tools in biotechnology and molecular medicine, e.g. for targeted gene knock-out/knock-down, gene delivery or gene therapy systems (4,9,22–25), and may as well be the targets for therapeutics (26). …”

Section: Introductionmentioning

confidence: 99%

Survey of group I and group II introns in 29 sequenced genomes of the Bacillus cereus group: insights into their spread and evolution

Tourasse

Kolstø

2008

Nucleic Acids Research

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Group I and group II introns are different catalytic self-splicing and mobile RNA elements that contribute to genome dynamics. In this study, we have analyzed their distribution and evolution in 29 sequenced genomes from the Bacillus cereus group of bacteria. Introns were of different structural classes and evolutionary origins, and a large number of nearly identical elements are shared between multiple strains of different sources, suggesting recent lateral transfers and/or that introns are under a strong selection pressure. Altogether, 73 group I introns were identified, inserted in essential genes from the chromosome or newly described prophages, including the first elements found within phages in bacterial plasmids. Notably, bacteriophages are an important source for spreading group I introns between strains. Furthermore, 77 group II introns were found within a diverse set of chromosomal and plasmidic genes. Unusual findings include elements located within conserved DNA metabolism and repair genes and one intron inserted within a novel retroelement. Group II introns are mainly disseminated via plasmids and can subsequently invade the host genome, in particular by coupling mobility with host cell replication. This study reveals a very high diversity and variability of mobile introns in B. cereus group strains.

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New approaches to targeting RNA with oligonucleotides: Inhibition of group I intron self‐splicing

Cited by 19 publications

References 98 publications

Revision of AMBER Torsional Parameters for RNA Improves Free Energy Predictions for Tetramer Duplexes with GC and iGiC Base Pairs

Revision of AMBER Torsional Parameters for RNA Improves Free Energy Predictions for Tetramer Duplexes with GC and iGiC Base Pairs

Identification of potential conserved RNA secondary structure throughout influenza A coding regions

Survey of group I and group II introns in 29 sequenced genomes of the Bacillus cereus group: insights into their spread and evolution

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