Skip to main content Accessibility help
×
Home

Bridging the gap between in vitro and in vivo RNA folding

  • Kathleen A. Leamy (a1) (a2), Sarah M. Assmann (a2) (a3) (a4), David H. Mathews (a5) and Philip C. Bevilacqua (a1) (a2) (a4) (a6)

Abstract

Deciphering the folding pathways and predicting the structures of complex three-dimensional biomolecules is central to elucidating biological function. RNA is single-stranded, which gives it the freedom to fold into complex secondary and tertiary structures. These structures endow RNA with the ability to perform complex chemistries and functions ranging from enzymatic activity to gene regulation. Given that RNA is involved in many essential cellular processes, it is critical to understand how it folds and functions in vivo. Within the last few years, methods have been developed to probe RNA structures in vivo and genome-wide. These studies reveal that RNA often adopts very different structures in vivo and in vitro, and provide profound insights into RNA biology. Nonetheless, both in vitro and in vivo approaches have limitations: studies in the complex and uncontrolled cellular environment make it difficult to obtain insight into RNA folding pathways and thermodynamics, and studies in vitro often lack direct cellular relevance, leaving a gap in our knowledge of RNA folding in vivo. This gap is being bridged by biophysical and mechanistic studies of RNA structure and function under conditions that mimic the cellular environment. To date, most artificial cytoplasms have used various polymers as molecular crowding agents and a series of small molecules as cosolutes. Studies under such in vivo-like conditions are yielding fresh insights, such as cooperative folding of functional RNAs and increased activity of ribozymes. These observations are accounted for in part by molecular crowding effects and interactions with other molecules. In this review, we report milestones in RNA folding in vitro and in vivo and discuss ongoing experimental and computational efforts to bridge the gap between these two conditions in order to understand how RNA folds in the cell.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Bridging the gap between in vitro and in vivo RNA folding
      Available formats
      ×

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Bridging the gap between in vitro and in vivo RNA folding
      Available formats
      ×

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Bridging the gap between in vitro and in vivo RNA folding
      Available formats
      ×

Copyright

Corresponding author

*Author for correspondence: Philip C. Bevilacqua, Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA and Center for RNA Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA. Tel.: 1-814-863-3812; Fax: 1-814-865-2927; Email: pcb5@psu.edu

References

Hide All
Alberts, B., Bray, D., Lewis, J., Roberts, K. & Watson, J. D. (1994). Molecular Biology of the Cell, 3rd edn. Garland Publishing, New York and London.
Andronescu, M., Condon, A., Turner, D. H. & Mathews, D. H. (2014). The determination of RNA folding nearest neighbor parameters. Methods in Molecular Biology 1097, 4570.
Baird, N. J., Westhof, E., Qin, H., Pan, T. & Sosnick, T. R. (2005). Structure of a folding intermediate reveals the interplay between core and peripheral elements in RNA folding. Journal of Molecular Biology 352, 712722.
Banerjee, A. R., Jaeger, J. A. & Turner, D. H. (1993). Thermal unfolding of a group 1 ribozyme: the low-temperature transition is primarily disruption of the tertiary structure. Biochemistry 32, 153163.
Banerjee, A. R. & Turner, D. H. (1995). The time dependence of chemical modification reveals slow steps in the folding of a Group I ribozyme. Biochemistry 34, 65046512.
Bellaousov, S. & Mathews, D. H. (2010). ProbKnot: fast prediction of RNA secondary structure including pseudoknots. RNA 16, 18701880.
Bernhart, S. H., Hofacker, I. L., Will, S., Gruber, A. R. & Stadler, P. F. (2008). RNAalifold: improved consensus structure prediction for RNA alignments. BMC Bioinformatics 9, 474.
Bloomfield, V. A., Crothers, D. M. & Tinoco, I. J. (2000). Nucleic Acids: Structures, Properties, and Functions. Sausalito, California: University Science Books.
Brion, P. & Westhof, E. (1997). Hierarchy and dynamics of RNA folding. Annual Review of Biophysics and Biomolecular Structure 26, 113137.
Buxbaum, A. R., Haimovich, G. & Singer, R. H. (2015). In the right place at the right time: visualizing and understanding mRNA localization. Nature Reviews. Molecular Cell Biology 16, 95109.
Cao, Y. & Woodson, S. A. (1998). Destabilizing effect of an rRNA stem-loop on an attenuator hairpin in the 5′ exon of the Tetrahymena pre-rRNA. RNA 4, 901914.
Chadalavada, D. M., Cerrone-Szakal, A. L. & Bevilacqua, P. C. (2007). Wild-type is the optimal sequence of the HDV ribozyme under cotranscriptional conditions. RNA 13, 21892201.
Chadalavada, D. M., Knudsen, S. M., Nakano, S.-I. & Bevilacqua, P. C. (2000). A role for upstream RNA structure in facilitating the catalytic fold of the genomic hepatitis delta virus ribozyme. Journal of Molecular Biology 301, 349367.
Chadalavada, D. M., Senchak, S. E. & Bevilacqua, P. C. (2002). The folding pathway of the genomic hepatitis delta virus ribozyme is dominated by slow folding of the pseudoknots1. Journal of Molecular Biology 317, 559575.
Chauhan, S. & Woodson, S. A. (2008). Tertiary interactions determine the accuracy of RNA folding. Journal of the American Chemical Society 130, 12961303.
Choi, W.-G., Swanson, S. J. & Gilroy, S. (2012). High-resolution imaging of Ca2+, redox status, ROS, and pH using GFP biosensors. The Plant Journal 70, 118128.
Clatterbuck Soper, S. F., Dator, R. P., Limbach, P. A. & Woodson, S. A. (2013). In vivo X-ray footprinting of pre-30S ribosomes reveals chaperone-dependent remodeling of late assembly intermediates. Molecular Cell 52, 506516.
Cordero, P. & Das, R. (2015). Rich RNA structure landscapes revealed by mutate-and-map analysis. PLoS Computational Biology 11, e1004473.
Cordero, P., Kladwang, W., Vanlang, C. C. & Das, R. (2012). Quantitative dimethyl sulfate mapping for automated RNA secondary structure inference. Biochemistry 51, 70377039.
Crothers, D. M., Cole, P. E., Hilbers, C. W. & Shulman, R. G. (1974). The molecular mechanism of thermal unfolding of Escherichia coli formylmethionine transfer RNA. Journal of Molecular Biology 87, 6388.
Dawson, W. K. & Bujnicki, J. M. (2016). Computational modeling of RNA 3D structures and interactions. Current Opinion in Structural Biology 37, 2228.
Deigan, K. E., Li, T. W., Mathews, D. H. & Weeks, K. M. (2009). Accurate SHAPE-directed RNA structure determination. Proceedings of the National Academy of Sciences of the United States of America 106, 97102.
De Michele, R., Carimi, F. & Frommer, W. B. (2014). Mitochondrial biosensors. The International Journal of Biochemistry & Cell Biology 48, 3944.
Denning, E. J., Thirumalai, D. & Mackerell, A. D. (2013). Protonation of trimethylamine N-oxide (TMAO) is required for stabilization of RNA tertiary structure. Biophysical Chemistry 184, 816.
Desai, R., Kilburn, D., Lee, H.-T. & Woodson, S. (2014). Increased ribozyme acitivty in crowded solutions. Journal of Biological Chemistry 289, 29722977.
Diamond, J. M., Turner, D. H. & Mathews, D. H. (2001). Thermodynamics of three-way multibranch loops in RNA. Biochemistry 40, 69716981.
Ding, Y., Kwok, C. K., Tang, Y., Bevilacqua, P. C. & Assmann, S. M. (2015). Genome-wide profiling of in vivo RNA structure at single-nucleotide resolution using Structure-seq. Nature Protocols 10, 10501066.
Ding, Y. & Lawrence, C. E. (2003). A statistical sampling algorithm for RNA secondary structure prediction. Nucleic Acids Research 31, 72807301.
Ding, Y., Tang, Y., Kwok, C. K., Zhang, Y., Bevilacqua, P. C. & Assmann, S. M. (2014). In vivo genome-wide profiling of RNA secondary structure reveals novel regulatory features. Nature 505, 696700.
Do, C. B., Foo, C. S. & Batzoglou, S. (2008). A max-margin model for efficient simultaneous alignment and folding of RNA sequences. Bioinformatics 24, i68i76.
Doshi, K. J., Cannone, J. J., Cobaugh, C. W. & Gutell, R. R. (2004). Evaluation of the suitability of free-energy minimization using nearest-neighbor energy parameters for RNA secondary structure prediction. BMC Bioinformatics 5, 105.
Doudna, J. A. & Cech, T. R. (2002). The chemical repertoire of natural ribozymes. Nature 418, 222228.
Dupuis, N. F., Holmstrom, E. D. & Nesbitt, D. J. (2014). Molecular-crowding effects on single-molecule RNA folding/unfolding thermodynamics and kinetics. Proceedings of the National Academy of Sciences of the United States of America 111, 84648469.
Dyer, R. B. & Brauns, E. B. (2009). Laser-induced temperature jump infrared measurements of RNA folding. Methods in Enzymology 469, 353372.
Eddy, S. R. (2004). How do RNA folding algorithms work? Nature Biotechnology 22, 14571458.
Eddy, S. R. (2014). Computational analysis of conserved RNA secondary structure in transcriptomes and genomes. Annual Review of Biophysics 43, 433456.
Ehresmann, C., Baudin, F., Mougel, M., Romby, P., Ebel, J. P. & Ehresmann, B. (1987). Probing the structure of RNAs in solution. Nucleic Acids Research 15, 91099128.
Fang, R., Moss, W. N., Rutenberg-Schoenberg, M. & Simon, M. D. (2015). Probing Xist RNA structure in cells using targeted structure-seq. PLoS Genetics 11, e1005668.
Fehr, M., Lalonde, S., Lager, I., Wolff, M. W. & Frommer, W. B. (2003). In vivo imaging of the dynamics for glucose uptake in the cytosol of COS-7 cells by fluorescent nanosensors. Journal of Biological Chemistry 278, 1912719133.
Feig, A. L. & Uhlenbeck, O. C. (1999). The role of metal ions in RNA biochemistry. In The RNA World, 2nd edn (eds. Gesteland, R. F., Cech, T. R. & Atkins, J. F.), pp. 287320. New York: Cold Spring Harbor Laboratory Press.
Fimognari, C. (2015). Role of oxidative RNA damage in chronic-degenerative diseases. Oxidative Medicine and Cellular Longevity 2015, 8.
Frankel, E. A., Bevilacqua, P. C. & Keating, C. D. (2016). Polyamine/nucleotide coacervates provide strong compartmentalization of Mg2+, nucleotides, and RNA. Langmuir 32, 20412049.
Freier, S. M., Kierzek, R., Caruthers, M. H., Neilson, T. & Turner, D. H. (1986a). Free energy contributions of G.U. and other terminal mismatches to helix stability. Biochemistry 25, 32093223.
Freier, S. M., Kierzek, R., Jaeger, J. A., Sugimoto, N., Caruthers, M. H., Neilson, T. & Turner, D. H. (1986b). Improved free-energy parameters for predictions of RNA duplex stability. Proceedings of the National Academy of Sciences of the United States of America 83, 93739377.
Fu, Y., Sharma, G. & Mathews, D. H. (2014). Dynalign II: common secondary structure prediction for RNA homologs with domain insertions. Nucleic Acids Research 42, 1393913948.
Gao, M., Gnutt, D., Orban, A., Appel, B., Righetti, F., Winter, R., Narberhaus, F., Müller, S. & Ebbinghaus, S. (2016). RNA hairpin folding in the crowded cell. Angewandte Chemie International Edition 55, 32243228.
Garst, A. D., Edwards, A. L. & Batey, R. T. (2011). Riboswitches: structures and mechanisms. Cold Spring Harbor Perspectives in Biology 3, a003533.
Gerstberger, S., Hafner, M. & Tuschl, T. (2014). A census of human RNA-binding proteins. Nature Reviews Genetics 15, 829845.
Guerrier-Takada, C., Gardiner, K., Marsh, T., Pace, N. & Altman, S. (1983). The RNA moiety of ribonuclease P is the catalytic subunit of the enzyme. Cell 35, 849857.
Hafner, M., Landthaler, M., Burger, L., Khorshid, M., Hausser, J., Berninger, P., Rothballer, A., Ascano, M. Jr., Jungkamp, A.-C., Munschauer, M., Ulrich, A., Wardle, G. S., Dewell, S., Zavolan, M. & Tuschl, T. (2010). Transcriptome-wide identification of RNA-binding protein and MicroRNA target sites by PAR-CLIP. Cell 141, 129141.
Hajdin, C. E., Bellaousov, S., Huggins, W., Leonard, C. W., Mathews, D. H. & Weeks, K. M. (2013). Accurate SHAPE-directed RNA secondary structure modeling, including pseudoknots. Proceedings of the National Academy of Sciences of the United States of America 110, 54985503.
Hajiaghayi, M., Condon, A. & Hoos, H. H. (2012). Analysis of energy-based algorithms for RNA secondary structure prediction. BMC Bioinformatics 13, 22.
Halvorsen, M., Martin, J. S., Broadaway, S. & Laederach, A. (2010). Disease-associated mutations that alter the RNA structural ensemble. PLoS Genetics 6, e1001074.
Harmanci, A. O., Sharma, G. & Mathews, D. H. (2008). PARTS: probabilistic alignment for RNA joinT secondary structure prediction. Nucleic Acids Research 36, 24062417.
Harmanci, A. O., Sharma, G. & Mathews, D. H. (2011). TurboFold: iterative probabilistic estimation of secondary structures for multiple RNA sequences. BMC Bioinformatics 12, 108.
Herschlag, D. & Cech, T. R. (1990). Catalysis of RNA cleavage by the Tetrahymena thermophil ribozyme. 1. Kinetic description of the reaction of an RNA substrate complementary to the active site. Biochemistry 29, 1015910171.
Hilbers, C. W., Robillard, G. T., Shulman, R. G., Blake, R. D., Webb, P. K., Fresco, R. & Riesner, D. (1976). Thermal unfolding of yeast glycine transfer RNA. Biochemistry 15, 18741882.
Holmstrom, E. D., Dupuis, N. F. & Nesbitt, D. J. (2015). Kinetic and thermodynamic origins of osmolyte-influenced nucleic acid folding. Journal of Physical Chemistry B 119, 36873696.
Hoseini, S. S. & Sauer, M. G. (2015). Molecular cloning using polymerase chain reaction, an educational guide for cellular engineering. Journal of Biological Engineering 9, 113.
Hu, B., Hu, L.-L., Chen, M.-L. & Wang, J.-H. (2013). A FRET ratiometric fluorescence sensing system for mercury detection and intracellular colorimetric imaging in live Hela cells. Biosensors and Bioelectronics 49, 499505.
Hull, C. M., Anmangandla, A. & Bevilacqua, P. C. (2016). Bacterial riboswitches and ribozymes potently activate the human innate immune sensor PKR. ACS Chemical Biology 11, 11181127.
Hull, C. M. & Bevilacqua, P. C. (2015). Mechanistic analysis of activation of the innate immune sensor PKR by bacterial RNA. Journal of Molecular Biology 427, 35013515.
Hull, C. M. & Bevilacqua, P. C. (2016). Discriminating self and non-self by RNA: roles for RNA structure, misfolding, and modification in regulating the innate immune sensor PKR. Accounts of Chemical Research, doi: 10.1021/acs.accounts.6b00151.
Imamura, H., Huynh Nhat, K. P., Togawa, H., Saito, K., Iino, R., Kato-Yamada, Y., Nagai, T. & Noji, H. (2009). Visualization of ATP levels inside single living cells with fluorescence resonance energy transfer-based genetically encoded indicators. Proceedings of the National Academy of Sciences of the United States of America 106, 1565115656.
Incarnato, D., Neri, F., Anselmi, F. & Oliviero, S. (2014). Genome-wide profiling of mouse RNA secondary structures reveals key features of the mammalian transcriptome. Genome Biology 15, 113.
Jaeger, J. A., Zuker, M. & Turner, D. H. (1990). Melting and chemical modification of a cyclized self-splicing group I intron: similarity of structures in 1 M Na+, in 10 mM Mg2+, and in the presence of substrate. Biochemistry 29, 1014710158.
Jaspers, P. & Kangasjärvi, J. (2010). Reactive oxygen species in abiotic stress signaling. Physiologia Plantarum 138, 405413.
Jiang, T., Kennedy, S. D., Moss, W. N., Kierzek, E. & Turner, D. H. (2014). Secondary structure of a conserved domain in an intron of influenza A M1 mRNA. Biochemistry 53, 52365248.
Kertesz, M., Wan, Y., Mazor, E., Rinn, J. L., Nutter, R. C., Chang, H. Y. & Segal, E. (2010). Genome-wide measurement of RNA secondary structure in yeast. Nature 467, 103107.
Kilburn, D., Roh, J. H., Behrouzi, R., Briber, R. M. & Woodson, S. A. (2013). Crowders perturb the entropy of RNA energy landscapes to favor folding. Journal of the American Chemical Society 135, 1005510063.
Kilburn, D., Roh, J. H., Guo, L., Briber, R. & Woodson, S. (2010). Molecular crowding stabilizes folded RNA structure by the excluded volume efect. Journal of the American Chemical Society 132, 86908696.
Kim, S. H., Quigley, G. J., Suddath, F. L., Mcpherson, A., Sneden, D., Kim, J. J., Weinzierl, J. & Rich, A. (1973). Three-dimensional structure of yeast phenylalanine transfer RNA: folding of the polynucleotide chain. Science 179, 285288.
Klostermeier, D. & Millar, D. P. (2001). RNA conformation and folding studied with fluorescence resonance energy transfer. Methods 23, 240254.
Koga, S., Williams, D. S., Perriman, A. W. & Mann, S. (2011). Peptide-nucleotide microdroplets as a step towards a membrane-free protocell model. Nature Chemistry 3, 720724.
Kubodera, T., Watanabe, M., Yoshiuchi, K., Yamashita, N., Nishimura, A., Nakai, S., Gomi, K. & Hanamoto, H. (2003). Thiamine-regulated gene expression of Aspergillus oryzae thiA requires splicing of the intron containing a riboswitch-like domain in the 5′-UTR. FEBS Letters 555, 516520.
Kutchko, K. M., Sanders, W., Ziehr, B., Phillips, G., Solem, A., Halvorsen, M., Weeks, K. M., Moorman, N. & Laederach, A. (2015). Multiple conformations are a conserved and regulatory feature of the RB1 5′ UTR. RNA 21, 12741285.
Kwok, C. K., Ding, Y., Tang, Y., Assmann, S. M. & Bevilacqua, P. C. (2013). Determination of in vivo RNA structure in low-abundance transcripts. Nature Communications 4, doi: 10.1038/ncomms3971.
Kwok, C. K., Tang, Y., Assmann, S. M. & Bevilacqua, J. M. (2015). The RNA structurome: transcriptome-wide structure probing with next-generation sequencing. Trends in Biochemical Sciences 40, 221232.
Lager, I., Looger, L. L., Hilpert, M., Lalonde, S. & Frommer, W. B. (2006). Conversion of a putative agrobacterium sugar-binding protein into a FRET sensor with high selectivity for sucrose. Journal of Biological Chemistry 281, 3087530883.
Lambert, D. & Draper, D. E. (2007). Effects of osmolytes on RNA secondary and tertiary structure stabilities and RNA-Mg2+ ion interactions. Journal of Molecular Biology 370, 9931005.
Lambert, D. & Draper, D. E. (2012). Denaturation of RNA secondary and tertiary structure by urea: simple unfolded state models and free energy parameters account for measured m-values. Biochemistry 51, 90149026.
Lambert, D., Leipply, D. & Draper, D. E. (2010). The osmolyte TMAO stabilizes native RNA tertiary structures in the absence of Mg2+: evidence for a large barrier to folding form phosphate dehydration. Journal of Molecular Biology 404, 138157.
Lavender, C. A., Gorelick, R. J. & Weeks, K. M. (2015a). Structure-based alignment and consensus secondary structures for three HIV-related RNA genomes. PLoS Computational Biology 11, e1004230.
Lavender, C. A., Lorenz, R., Zhang, G., Tamayo, R., Hofacker, I. L. & Weeks, K. M. (2015b). Model-free RNA sequence and structure alignment informed by SHAPE probing reveals a conserved alternate secondary structure for 16S rRNA. PLoS Computational Biology 11, e1004126.
Levitt, M. (1969). Detailed molecular model for transfer ribonucleic acid. Nature 224, 759763.
Li, C., Wen, A., Shen, B., Lu, J., Huang, Y. & Chang, Y. (2011). FastCloning: a highly simplified, purification-free, sequence- and ligation-independent PCR cloning method. BMC Biotechnology 11, 110.
Li, F., Zheng, Q., Vandivier, L. E., Willmann, M. R., Chen, Y. & Gregory, B. D. (2012). Regulatory impact of RNA secondary structure across the Arabidopsis transcriptome. The Plant Cell 24, 43464359.
Licatalosi, D. D., Mele, A., Fak, J. J., Ule, J., Kayikci, M., Chi, S. W., Clark, T. A., Schweitzer, A. C., Blume, J. E., Wang, X., Darnell, J. C. & Darnell, R. B. (2008). HITS-CLIP yields genome-wide insights into brain alternative RNA processing. Nature 456, 464469.
Lindenburg, L. H., Vinkenborg, J. L., Oortwijn, J., Aper, S. J. A. & Merkx, M. (2013). MagFRET: the first genetically encoded fluorescent Mg(2+) sensor. PLoS ONE 8, e82009.
Liu, B., Diamond, J. M., Mathews, D. H. & Turner, D. H. (2011). Fluorescence competition and optical melting measurements of RNA three-way multibranch loops provide a revised model for thermodynamic parameters. Biochemistry 50, 640653.
Liu, B., Mathews, D. H. & Turner, D. H. (2010a). RNA pseudoknots: folding and finding. F1000 Biology Reports 2, 8.
Liu, B., Shankar, N. & Turner, D. H. (2010b). Fluorescence competition assay measurements of free energy changes for RNA pseudoknots. Biochemistry 49, 623634.
London, R. E. (1991). Methods for measurement of intracellular magnesium: NMR and fluorescence. Annual Reviews of Physiology 53, 241258.
Lorenz, R., Wolfinger, M. T., Tanzer, A. & Hofacker, I. L. (2016). Predicting RNA secondary structures from sequence and probing data. Methods.
Lu, Z. J., Gloor, J. W. & Mathews, D. H. (2009). Improved RNA secondary structure prediction by maximizing expected pair accuracy. RNA 15, 18051813.
Lu, Z. J., Turner, D. H. & Mathews, D. H. (2006). A set of nearest neighbor parameters for predicting the enthalpy change of RNA secondary formation. Nucleic Acids Research 34, 49124924.
Lusk, J. E., Williams, R. J. & Kennedy, E. P. (1968). Magnesium and the growth of Escherichia coli . Journal of Biological Chemistry 243, 26182624.
Mahen, E. M., Harger, J. W., Calderon, E. M. & Fedor, M. J. (2005). Kinetics and thermodynamics make different contributions to RNA folding in vitro and in yeast. Molecular Cell 19, 2737.
Mathews, D. H. (2004). Using an RNA secondary structure partition function to determine confidence in base pairs predicted by free energy minimization. RNA 10, 11781190.
Mathews, D. H. (2006). Revolutions in RNA secondary structure prediction. Journal of Molecular Biology 359, 526532.
Mathews, D. H., Disney, M. D., Childs, J. L., Schroeder, S. J., Zuker, M. & Turner, D. H. (2004). Incorporating chemical modification constraints into a dynamic programming algorithm for prediction of RNA secondary structure. Proceedings of the National Academy of Sciences of the United States of America 101, 72877292.
Matteucci, M. D. & Caruthers, M. H. (1981). Synthesis of deoxyoligonucleotides on a polymer support. Journal of the American Chemical Society 103, 31853191.
Mccaskill, J. S. (1990). The equilibrium partition function and base pair probabilities for RNA secondary structure. Biopolymers 29, 11051119.
Merino, E. J., Wilkinson, K. A., Coughlan, J. L. & Weeks, K. M. (2005). RNA structure analysis at single nucleotide resolution by selective 2′-hydoxyl acylation and primer extension (SHAPE). Journal of the American Chemical Society 127, 42234231.
Miao, Z., Adamiak, R. W., Blanchet, M.-F., Boniecki, M., Bujnicki, J. M., Chen, S.-J., Cheng, C., Chojnowski, G., Chou, F.-C., Cordero, P., Cruz, J. A., Ferré-D'amaré, A. R., Das, R., Ding, F., Dokholyan, N. V., Dunin-Horkawicz, S., Kladwang, W., Krokhotin, A., Lach, G., Magnus, M., Major, F., Mann, T. H., Masquida, B., Matelska, D., Meyer, M., Peselis, A., Popenda, M., Purzycka, K. J., Serganov, A., Stasiewicz, J., Szachniuk, M., Tandon, A., Tian, S., Wang, J., Xiao, Y., Xu, X., Zhang, J., Zhao, P., Zok, T. & Westhof, E. (2015). RNA-puzzles round II: assessment of RNA structure prediction programs applied to three large RNA structures. RNA 21, 10661084.
Milligan, J. F., Groebe, D. R., Witherell, G. W. & Uhlenbeck, O. C. (1987). Oligoribonucleotide synthesis using T7 RNA polymerase and synthetic DNA templates. Nucleic Acids Research 15, 87838798.
Minton, A. P. (2001). The influence of macromolecular crowding and macromolecular confinement on biochemical media. Journal of Biological Chemistry 276, 1057710589.
Mitchell, D. I., Jarmoskaite, I., Seval, N., Seifert, S. & Russell, R. (2013). The long-range P3 helix of the Tetrahymena ribozyme is disrupted during folding between the native and misfolded conformations. Journal of Molecular Biology 425, 26702686.
Mitchell, D. I. & Russell, R. (2014). Folding pathways of the Tetrahymena ribozyme. Journal of Molecular Biology 426, 23002312.
Moazed, D., Stern, S. & Noller, H. F. (1986a). Rapid chemical probing of conformation in 16S ribosomal RNA and 30S ribosomal subunits using primer extension. Journal of Molecular Biology 187, 399416.
Moazed, D., Stern, S. & Noller, H. F. (1986b). Rapid chemical probing of conformation in 16S ribosomal RNA and 30S ribosomal subunits using primer extension. Journal of Molecular Biology 187, 399416.
Moore, M. & Sharp, P. (1992). Site-specific modification of pre-mRNA: the 2′-hydroxyl groups at the splice sites. Science 256, 992997.
Mullis, K. B. (1990). The unusual origin of the polymerase chain reaction. Scientific American 262, 5661, 64–65.
Nadarajan, S. P., Ravikumar, Y., Deepankumar, K., Lee, C.-S. & Yun, H. (2014). Engineering lead-sensing GFP through rational designing. Chemical Communications 50, 1597915982.
Nakano, S.-I., Karimata, H. T., Kitagawa, Y. & Sugimoto, N. (2009). Facilitation of RNA enzyme activity in the molecular crowding media of cosolutes. Journal of the American Chemical Society 131, 1688116888.
Nakano, S.-I., Kitagawa, Y., Yamashita, H., Miyoshi, D. & Sugimoto, N. (2015). Effects of cosolvents on the folding and catalytic activities of the hammerhead ribozyme. ChemBioChem 16, 18031810.
Nakano, S.-I., Miyoshi, D. & Sugimoto, N. (2014). Effects of molecular crowding on the structures, interactions, and functions of nucleic acids. Chemical Reviews 114, 27332758.
Nallagatla, S. R., Hwang, J., Toroney, R., Zheng, X., Cameron, C. E. & Bevilacqua, P. C. (2007). 5′-triphosphate-dependent activation of PKR by RNAs with short stem-loops. Science 318, 14551458.
Nick, H. & Gilbert, W. (1985). Detection in vivo of protein–DNA interactions within the lac Operon of Escherichia coli . Nature 313, 795798.
Nissen, P., Hansen, J., Ban, N., Moore, P. B. & Steitz, T. A. (2000). The structural basis of ribosome activity in peptide bond synthesis. Science 289, 920930.
Novikova, I. V., Hennelly, S. P. & Sanbonmatsu, K. Y. (2012). Structural architecture of the human long non-coding RNA, steroid receptor RNA activator. Nucleic Acids Research 40, 50345051.
Osborne, R. J. & Thornton, C. A. (2006). RNA-dominant diseases. Human Molecular Genetics 15, R162R169.
Ouyang, Z., Snyder, M. P. & Chang, H. Y. (2013). SeqFold: genome-scale reconstruction of RNA secondary structure integrating high-throughput sequencing data. Genome Research 23, 377387.
Paige, J. S., Duc, T. N., Song, W. & Jaffrey, S. R. (2012). Fluorescence imaging of cellular metabolites with RNA. Science (New York, NY) 335, 11941194.
Paige, J. S., Wu, K. & Jaffrey, S. R. (2011). RNA mimics of green fluorescent protein. Science (New York, NY) 333, 642646.
Paudel, B. P. & Rueda, D. (2014). Molecular crowding accelerates ribozymes docking and catalysis. Journal of the American Chemical Society 136, 1670016703.
Pollack, L. (2011). Time resolved SAXS and RNA folding. Biopolymers 95, 543549.
Pouvreau, S. (2014). Genetically encoded reactive oxygen species (ROS) and redox indicators. Biotechnology Journal 9, 282293.
Rangan, P., Masuida, B., Westhof, E. & Woodson, S. A. (2003). Assembly of core helices and rapid tertiary folding of a small bacterial group I ribozyme. Proceedings of the National Academy of Sciences of the United States of America 100, 15741579.
Record, M. T. J., Courtenay, E. S., Cayley, S. D. & Guttman, H. J. (1998). Responses of E. coli to osmotic stress: large changes in amounts of cytoplasmic solutes and water. Trends in Biochemical Sciences 23, 143148.
Reeder, J. & Giegerich, R. (2005). Consensus shapes: an alternative to the Sankoff algorithm for RNA consensus structure prediction. Bioinformatics 21, 35163523.
Reeder, J., Hochsmann, M., Rehmsmeier, M., Voss, B. & Giegerich, R. (2006). Beyond Mfold: recent advances in RNA bioinformatics. Journal of Biotechnology 124, 4155.
Reyes, F. E., Garst, A. D. & Batey, R. T. (2009). Chapter 6 – strategies in RNA crystallography. Methods in Enzymology 469, 119139.
Richards, E. G., Flessel, C. P. & Fresco, J. R. (1963). Polynucleotides. IV. Molecular properties and conformations of polyribonucleic acids. Biopolymers 1, 431446.
Robertus, J. D., Ladner, J. E., Finch, J. T., Rhodes, D., Brown, R. S., Clark, B. F. C. & Klug, A. (1974). Structure of yeast phenylalanine tRNA at 3 Å resolution. Nature 250, 546551.
Roh, J. H., Guo, L., Kilburn, D., Briber, R., Irving, T. & Woodson, S. (2010). Multistage collapse of a bacterial ribozyme observed by time-resolved small-angle X-ray scattering. Journal of the American Chemical Society 132, 1014810154.
Romani, A. M. (2007). Magnesium homeostasis in mammalian cells. Frontiers in Bioscience 12, 308331.
Rook, M. S., Treiber, D. K. & Williamson, J. R. (1998). Fast folding mutants of the Tetrahymena group I ribozyme reveal a rugged folding energy landscape. Journal of Molecular Biology 281, 609620.
Roth, A., Weinberg, Z., Chen, A. G. Y., Kim, P. B., Ames, T. D. & Breaker, R. R. (2014). A widespread self-cleaving ribozymes class is revealed by bioinformatics. Nature Chemical Biology 10, 5660.
Rouskin, S., Zubradt, M., Washietl, S., Kellis, M. & Weissman, J. S. (2014). Genome-wide probing of RNA structure reveals active unfolding of mRNA structures in vivo . Nature 505, 701705.
Roy, R., Hohng, S. & Ha, T. (2008). A practical guide to single-molecule FRET. Nature Methods 5, 507516.
Salehi-Ashtiani, K., Luptak, A., Litovchick, A. & Szostak, J. W. (2006). A genomewide search for ribozymes reveals an HDV-like sequence in the Human CPEB3 gene. Science 313, 17881792.
Santangelo, P., Nitin, N. & Bao, G. (2006). Nanostructured probes for RNA detection in living cells. Annals of Biomedical Engineering 34, 3950.
Scalvi, B., Woodson, S., Sullivan, M., Chance, M. R. & Brenowitz, M. (1997). Time-resolved synchrotron X-ray “footprinting”, a new approach to the study of nucleic acid structure and function: application to protein–DNA interactions and RNA folding. Journal of Molecular Biology 266, 144159.
Scaringe, S., Wincott, F. E. & Caruthers, M. H. (1998). Novel RNA synthesis method using 5′-O-silyl-2′-orthoester protecting groups. Journal of the American Chemical Society 120, 1182011821.
Schroeder, S. J. & Turner, D. H. (2000). Factors affecting the thermodynamic stability of small asymmetric internal loops in RNA. Biochemistry 39, 92579274.
Schroeder, S. J. & Turner, D. H. (2009). Optical melting measurements of nucleic acid thermodynamics. Methods in Enzymology 468, 371387.
Sclavi, B., Sullivan, M., Change, M. R., Brenowitz, M. & Woodson, S. (1998). RNA folding at millisecond intervals by synchrotron hydroxyl radical footprinting. Science 279, 19401943.
Seetin, M. G. & Mathews, D. H. (2012a). RNA structure prediction: an overview of methods. Methods in Molecular Biology 905, 99122.
Seetin, M. G. & Mathews, D. H. (2012b). TurboKnot: rapid prediction of conserved RNA secondary structures including pseudoknots. Bioinformatics 28, 792798.
Serganov, A. & Nudler, E. (2013). A decade of riboswitches. Cell 152, 1724.
Serganov, A. & Patel, D. (2007). Ribozymes, riboswitches and beyond: regulation of gene expression without proteins. Nature 8, 776790.
Serra, M. J., Baird, J. D., Dale, T., Fey, B. L., Retatagos, K. & Westhof, E. (2002). Effects of magnesium ions on the stabilization of RNA oligomers of defined structures. RNA 8, 307323.
Sherpa, C., Rausch, J. W., Le Grice, S. F. J., Hammarskjold, M.-L. & Rekosh, D. (2015). The HIV-1 Rev response element (RRE) adopts alternative conformations that promote different rates of virus replication. Nucleic Acids Research 43, 46764686.
Sierzchala, A., Dellinger, D. J., Betley, J. R., Wyrzykiewicz, T. K., Yamada, C. M. & Caruthers, M. H. (2003). Solid-phase oligodeoxynucleotide synthesis: a two-step cycle using peroxy anion deprotection. Journal of the American Chemical Society 125, 1342713441.
Sloma, M. F. & Mathews, D. H. (2015). Improving RNA secondary structure prediction with structure mapping data. Methods in Enzymology 553, 91114.
Solomatin, S. V., Greenfeld, M., Chu, S. & Herschlag, D. (2010). Multiple native states reveal persistent ruggedness of an RNA folding landscape. Nature 463, 681684.
Somarowthu, S., Legiewicz, M., Chillón, I., Marcia, M., Liu, F. & Pyle, A. M. (2015). HOTAIR forms an intricate and modular secondary structure. Molecular Cell 58, 353361.
Soto, A. M., Misra, V. & Draper, D. E. (2007). Tertiary structure of an RNA pseudoknot is stabilized by “diffuse” Mg2+ ions. Biochemistry 46, 29732983.
Spitale, R. C., Flynn, R. A., Zhang, Q. C., Crisalli, P., Lee, B., Jung, J.-W., Kuchelmeister, H. Y., Batista, P. J., Torre, E. A., Kool, E. T. & Chang, H. Y. (2015). Structural imprints in vivo decode RNA regulatory mechanisms. Nature 519, 486490.
Stael, S., Wurzinger, B., Mair, A., Mehlmer, N., Vothknecht, U. C. & Teige, M. (2011). Plant organellar calcium signalling: an emerging field. Journal of Experimental Botany 63, 15251542.
Stein, A. & Crothers, D. M. (1976). Conformational changes of transfer RNA. The role of magnesium(II). Biochemistry 15, 160168.
Strulson, C. A., Boyer, J. A., Whitman, E. E. & Bevilacqua, P. C. (2014). Molecular crowders and cosolutes promote folding cooperativity of RNA under physiological ionic conditions. RNA 20, 331347.
Strulson, C. A., Molden, R. C., Keating, C. D. & Bevilacqua, P. C. (2012). RNA catalysis through compartmentalization. Nature Chemistry 4, 941946.
Strulson, C. A., Yennawar, N. H., Rambo, R. P. & Bevilacqua, P. C. (2013). Molecular crowding favors reactivity of a human ribozyme under physiological ionic conditions. Biochemistry 52, 81878197.
Sükösd, Z., Andersen, E. S., Seemann, S. E., Jensen, M. K., Hansen, M., Gorodkin, J. & Kjems, J. (2015). Full-length RNA structure prediction of the HIV-1 genome reveals a conserved core domain. Nucleic Acids Research 43, 1016810179.
Sükösd, Z., Knudsen, B., Kjems, J. & Pedersen, C. N. S. (2012). PPfold 3·0: fast RNA secondary structure prediction using phylogeny and auxiliary data. Bioinformatics 28, 26912692.
Sussman, J. L., Holbrook, S. R., Warrant, W., Church, G. M. & Kim, S. H. (1978). Crystal structure of yeast phenylalanine transfer RNA. 1. Crystallographic refinement. Journal of Molecular Biology 123, 607630.
Suurkuusk, J., Alvarez, J., Freire, E. & Biltonen, R. (1977). Calorimetric determination of the heat capacity changes associated with the conformational transitions of polyriboadenylic acid and polyribouridylic acid. Biopolymers 16, 26412652.
Swanson, S. J., Choi, W.-G., Chanoca, A. & Gilroy, S. (2011). In vivo imaging of Ca2+, pH, and reactive oxygen species using fluorescent probes in plants. Annual Review of Plant Biology 62, 273297.
Swisher, J. F., Su, L. J., Brenowitz, M., Anderson, V. E. & Pyle, A. M. (2002). Productive folding to the native state by a Group II intron ribozyme. Journal of Molecular Biology 315, 297310.
Talkish, J., May, G., Lin, Y., Woolford, J. L. J. & Mcmanus, C. J. (2014). Mod-seq: high-throughput sequencing for chemical probind of RNA structure. RNA 20, 713720.
Tang, S., Reddish, F., Zhuo, Y. & Yang, J. J. (2015a). Fast kinetics of calcium signaling and sensor design. Current Opinion in Chemical Biology 27, 9097.
Tang, Y., Bouvier, E., Kwok, C. K., Ding, Y., Nekrutenko, A., Bevilacqua, P. C. & Assmann, S. M. (2015b). StructureFold: genome-wide RNA secondary structure mapping and reconstruction in vivo . Bioinformatics 31, 26682675.
Tanner, M. A. & Cech, T. R. (1996). Activity and thermostability of the small self-splicing group I intron in the pre-tRNAIle of the purple bacterium Azoarcus . RNA 2, 7483.
Tantama, M., Hung, Y. P. & Yellen, G. (2011). Imaging intracellular pH in live cells with a genetically encoded red fluorescent protein sensor. Journal of the American Chemical Society 133, 1003410037.
Tinoco, I. J. & Bustamante, C. (1999). How RNA folds. Journal of Molecular Biology 293, 271281.
Torarinsson, E., Havgaard, J. H. & Gorodkin, J. (2007). Multiple structural alignment and clustering of RNA sequences. Bioinformatics 23, 926932.
Treiber, D. K., Rook, M. S., Zarrinkar, P. P. & Williamson, J. R. (1998). Kinetic intermediates trapped by native interactions in RNA folding. Science 279, 19431946.
Truong, D. M., Sidote, D. J., Russell, R. & Lambowitz, A. M. (2013). Enhanced group II intron retrohoming in magnesium-deficient Escherichia coli via selection of mutations in the ribozyme core. Proceedings of the National Academy of Sciences of the United States of America 110, E3800E3809.
Tsien, R. Y. (2010). The 2009 Lindau Nobel Laureate Meeting: Roger Y. Tsien, Chemistry 2008. Journal of Visualized Experiments 13, 1575.
Turner, D. H. & Mathews, D. H. (2010). NNDB: the nearest neighbor parameter database for predicting stability of nucleic acidsecondary structure. Nucleic Acids Research 38, D280D282.
Tyrrell, J., Mcginnis, J. L., Weeks, K. M. & Pielak, G. J. (2013). The cellular environment stabilized adenine riboswitch RNA structure. Biochemistry 52, 87778785.
Tyrrell, J., Weeks, K. M. & Pielak, G. J. (2015). Challenge of mimicking the influence of the cellular environment on RNA structure by PEG-induced macromolecular crowding. Biochemistry 54, 64476453.
Underwood, J. G., Uzilov, A. V., Katzman, S., Onodera, C. S., Mainzer, J. E., Mathews, D. H., Lowe, T. M., Salama, S. R. & Haussler, D. (2010). FragSeq: transcriptome-wide RNA structure probing using high-throughput sequencing. Nature Methods 7, 9951001.
Walter, N. G. (2001). Structural dynamics of catalytic RNA highlighted by fluorescence resonance energy transfer. Methods 25, 1930.
Wan, Y., Kertesz, M., Spitale, R. C., Segal, E. & Chang, H. Y. (2011). Understanding the transcriptome through RNA structure. Nature Reviews Genetics 12, 641655.
Wan, Y., Qu, K., Ouyang, Z., Kertesz, M., Li, J., Tibshirani, R., Makino, D. L., Nutter, R. C., Segal, E. & Chang, H. Y. (2012). Genome-wide measurement of RNA folding energies. Molecular Cell 48, 169181.
Wan, Y., Qu, K., Zhang, Q. C., Flynn, R. A., Manor, O., Ouyang, Z., Zhang, J., Spitale, R. C., Snyder, M. P., Segal, E. & Chang, H. Y. (2014). Landscape and variation of RNA secondary structure across the human transcriptome. Nature 505, 706709.
Wan, Y., Suh, H., Russell, R. & Herschlag, D. (2010). Multiple unfolding events during native folding of the Tetrahymena group I ribozyme. Journal of Molecular Biology 400, 10671077.
Washietl, S., Hofacker, I. L., Stadler, P. F. & Kellis, M. (2012). RNA folding with soft constraints: reconciliation of probing data and thermodynamic secondary structure prediction. Nucleic Acids Research 40, 42614272.
Weeks, K. M. (2010). Advances in RNA secondary and tertiary structure analysis by chemical probing. Current Opinion in Structural Biology 20, 295304.
Weyn-Vanhentenryck, S. M., Mele, A., Yan, Q., Sun, S., Farny, N., Zhang, Z., Xue, C., Herre, M., Silver, P. A., Zhang, M. Q., Krainer, A. R., Darnell, R. B. & Zhang, C. (2014). HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism. Cell Reports 6, 11391152.
Wickiser, J. K., Cheah, M. T., Breaker, R. R. & Crothers, D. M. (2005a). The kinetics of ligand binding by an adenine-sensing riboswitch. Biochemistry 44, 1340413414.
Wickiser, J. K., Winkler, W. C., Breaker, R. R. & Crothers, D. M. (2005b) The speed of RNA transcription and metabolite binding kinetics operate an FMN riboswitch. Molecular Cell 18, 4960.
Will, S., Reiche, K., Hofacker, I. L., Stadler, P. F. & Backofen, R. (2007). Inferring noncoding RNA families and classes by means of genome-scale structure-based clustering. PLoS Computational Biology 3, e65.
Wu, Y., Shi, B., Ding, X., Liu, T., Hu, X., Yip, K. Y., Yang, Z. R., Mathews, D. H. & Lu, Z. J. (2015). Improved prediction of RNA secondary structure by integrating the free energy model with restraints derived from experimental probing data. Nucleic Acids Research 43, 72477259.
Wuchty, S., Fontana, W., Hofacker, I. L. & Schuster, P. (1999). Complete suboptimal folding of RNA and the stability of secondary structures. Biopolymers 49, 145165.
Xia, T., Santalucia, J., Burkard, M. E., Kierzek, R., Schroeder, S. J., Jiao, X., Cox, C. & Turner, D. H. (1998). Thermodynamic parameters for an expanded nearest-neighbor model for formation of RNA duplexes with Watson–Crick base pairs. Biochemistry 37, 1471914735.
Xu, Z. & Mathews, D. H. (2011). Multilign: an algorithm to predict secondary structures conserved in multiple RNA sequences. Bioinformatics 27, 626632.
Yancey, P. H., Clark, M. E., Hand, S. C., Bowlus, R. D. & Somero, G. N. (1982). Living with water stress: evolution of osmolyte systems. Science 217, 12141222.
Yang, S. (2014). Methods for SAXS-based structure determination of biomolecular complexes. Advanced Materials 26, 79027910.
Yang, Z., Cao, J., He, Y., Yang, J. H., Kim, T., Peng, X. & Kim, J. S. (2014). Macro-/micro-environment-sensitive chemosensing and biological imaging. Chemical Society Reviews 43, 45634601.
You, M. & Jaffrey, S. R. (2015). Structure and mechanism of RNA mimics of green fluorescent protein. Annual Review of Biophysics 44, 187206.
You, M., Litke, J. L. & Jaffrey, S. R. (2015). Imaging metabolite dynamics in living cells using a Spinach-based riboswitch. Proceedings of the National Academy of Sciences of the United States of America 112, E2756E2765.
Zarringhalam, K., Meyer, M. M., Dotu, I., Chuang, J. H. & Clote, P. (2012). Integrating chemical footprinting data into RNA secondary structure prediction. PLoS ONE 7, e45160.
Zarrinkar, P. P., Wang, J. & Williamson, J. R. (1996). Slow folding kinetics of RNase P RNA. RNA 2, 564573.
Zaug, A. & Cech, T. R. (1995). Analysis of the structure of Tetrahymena nuclear RNAs in vivo: telomerase RNA, the self-splicing rRNA intron, and U2 snRNA. RNA 1, 363374.
Zheng, Q., Ryvkin, P., Li, F., Dragomir, I., Valladares, O., Yang, J., Cao, K., Wang, L.-S. & Gregory, B. D. (2010). Genome-wide double-stranded RNA sequencing reveals the functional significance of base-paired RNAs in Arabidopsis . PLoS Genetics 6, e1001141.
Zhuang, X., Bartley, L. E., Babcock, H. P., Russell, R., Ha, T., Herschlag, D. & Chu, S. (2000). A single-molecule study of RNA catalysis and folding. Science 288, 20482051.
Zimmerman, S. B. & Trach, S. O. (1991). Estimation of macromolecule concentrations and excluded volume effects for the cytoplasm of Escherichia coli. Journal of Molecular Biology 222, 599620.
Zuker, M. (1989). On finding all suboptimal foldings of an RNA molecule. Science 244, 4852.

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed