Surprising Sequence Effects on GU Closure of Symmetric 2 × 2 Nucleotide RNA Internal Loops.

GU base pairs are important RNA structural motifs and often close loops. Accurate prediction of RNA structures relies upon understanding the interactions determining structure. The thermodynamics of some 2 × 2 nucleotide internal loops closed by GU pairs are not well understood. Here, several self-complementary oligonucleotide sequences expected to form duplexes with 2 × 2 nucleotide internal loops closed by GU pairs were investigated. Surprisingly, nuclear magnetic resonance revealed that many of the sequences exist in equilibrium between hairpin and duplex conformations. This equilibrium is not observed with loops closed by Watson-Crick pairs. To measure the thermodynamics of some 2 × 2 nucleotide internal loops closed by GU pairs, non-self-complementary sequences that preclude formation of hairpins were designed. The measured thermodynamics indicate that some internal loops closed by GU pairs are unusually unstable. This instability accounts for the observed equilibria between duplex and hairpin conformations. Moreover, it suggests that future three-dimensional structures of loops closed by GU pairs may reveal interactions that unexpectedly destabilize folding.

[1]  D. Turner,et al.  Molecular dynamics correctly models the unusual major conformation of the GAGU RNA internal loop and with NMR reveals an unusual minor conformation , 2018, RNA.

[2]  David H Mathews,et al.  Modeling RNA secondary structure folding ensembles using SHAPE mapping data , 2017, Nucleic acids research.

[3]  Robert D. Finn,et al.  Rfam 13.0: shifting to a genome-centric resource for non-coding RNA families , 2017, Nucleic Acids Res..

[4]  B. Klaholz,et al.  Visualization of chemical modifications in the human 80S ribosome structure , 2017, Nature.

[5]  Gaurav Sharma,et al.  TurboFold II: RNA structural alignment and secondary structure prediction informed by multiple homologs , 2017, Nucleic acids research.

[6]  David H Mathews,et al.  Physics‐based all‐atom modeling of RNA energetics and structure , 2017, Wiley interdisciplinary reviews. RNA.

[7]  Rhiju Das,et al.  RNA structure inference through chemical mapping after accidental or intentional mutations , 2017, Proceedings of the National Academy of Sciences.

[8]  Advancing viral RNA structure prediction: measuring the thermodynamics of pyrimidine-rich internal loops. , 2017, RNA.

[9]  Katarzyna J Purzycka,et al.  RNA-Puzzles Round III: 3D RNA structure prediction of five riboswitches and one ribozyme. , 2017, RNA.

[10]  S. Ranganathan,et al.  Advances in RNA molecular dynamics: a simulator's guide to RNA force fields , 2017, Wiley interdisciplinary reviews. RNA.

[11]  Michael F. Sloma,et al.  Exact calculation of loop formation probability identifies folding motifs in RNA secondary structures , 2016, RNA.

[12]  J. Frank,et al.  Structure and assembly model for the Trypanosoma cruzi 60S ribosomal subunit , 2016, Proceedings of the National Academy of Sciences.

[13]  Jessica L. Childs-Disney,et al.  Approaches to Validate and Manipulate RNA Targets with Small Molecules in Cells. , 2016, Annual review of pharmacology and toxicology.

[14]  S. Schroeder,et al.  Structures and Energetics of Four Adjacent G·U Pairs That Stabilize an RNA Helix. , 2015, The journal of physical chemistry. B.

[15]  Jonathan L Chen,et al.  Nuclear Magnetic Resonance-Assisted Prediction of Secondary Structure for RNA: Incorporation of Direction-Dependent Chemical Shift Constraints , 2015, Biochemistry.

[16]  Kevin Y. Yip,et al.  Improved prediction of RNA secondary structure by integrating the free energy model with restraints derived from experimental probing data , 2015, Nucleic acids research.

[17]  Feng Ding,et al.  RNA-Puzzles Round II: assessment of RNA structure prediction programs applied to three large RNA structures , 2015, RNA.

[18]  D. Turner,et al.  Stacking in RNA: NMR of Four Tetramers Benchmark Molecular Dynamics , 2015, Journal of chemical theory and computation.

[19]  Gabriele Varani,et al.  Structure based approaches for targeting non-coding RNAs with small molecules. , 2015, Current opinion in structural biology.

[20]  D. Mathews,et al.  Dynalign II: common secondary structure prediction for RNA homologs with domain insertions , 2014, Nucleic acids research.

[21]  J. Woolford,et al.  Mod-seq: high-throughput sequencing for chemical probing of RNA structure , 2014, RNA.

[22]  Alan Brown,et al.  Structure of the Yeast Mitochondrial Large Ribosomal Subunit , 2014, Science.

[23]  D. Turner,et al.  Structure determination of noncanonical RNA motifs guided by 1H NMR chemical shifts , 2014, Nature Methods.

[24]  Steven M. Gallo,et al.  Sequence-based design of bioactive small molecules that target precursor microRNAs , 2014, Nature chemical biology.

[25]  Y. Zhang,et al.  In vivo genome-wide profiling of RNA secondary structure reveals novel regulatory features , 2013, Nature.

[26]  Asaminew H. Aytenfisu,et al.  Modified Amber Force Field Correctly Models the Conformational Preference for Tandem GA pairs in RNA , 2014, Journal of chemical theory and computation.

[27]  Manolis Kellis,et al.  Genome-wide probing of RNA structure reveals active unfolding of mRNA structures in vivo , 2013, Nature.

[28]  Jan Gorodkin,et al.  RNA structural alignments, part I: Sankoff-based approaches for structural alignments. , 2014, Methods in molecular biology.

[29]  Kiyoshi Asai,et al.  RNA structural alignments, part II: non-Sankoff approaches for structural alignments. , 2014, Methods in molecular biology.

[30]  D. Turner.  Fundamental interactions in RNA: Questions answered and remaining. , 2013, Biopolymers.

[31]  D. Mathews,et al.  Accurate SHAPE-directed RNA secondary structure modeling, including pseudoknots , 2013, Proceedings of the National Academy of Sciences.

[32]  D. Turner,et al.  Novel Conformation of an RNA Structural Switch , 2012, Biochemistry.

[33]  D. Turner,et al.  Understanding the role of base stacking in nucleic acids. MD and QM analysis of tandem GA base pairs in RNA duplexes. , 2012, Physical chemistry chemical physics : PCCP.

[34]  Jonathan L Chen,et al.  Testing the Nearest Neighbor Model for Canonical RNA Base Pairs: Revision of GU Parameters , 2012, Biochemistry.

[35]  Feng Ding,et al.  RNA-Puzzles: a CASP-like evaluation of RNA three-dimensional structure prediction. , 2012, RNA.

[36]  Rhiju Das,et al.  Why Can’t We Predict RNA Structure At Atomic Resolution? , 2011, 1103.3032.

[37]  W. Webb,et al.  Ionic strength-dependent persistence lengths of single-stranded RNA and DNA , 2011, Proceedings of the National Academy of Sciences.

[38]  Rhiju Das,et al.  An enumerative stepwise ansatz enables atomic-accuracy RNA loop modeling , 2011, Proceedings of the National Academy of Sciences.

[39]  Peter F. Stadler,et al.  ViennaRNA Package 2.0 , 2011, Algorithms for Molecular Biology.

[40]  Paul J Jardine,et al.  Structure and assembly of the essential RNA ring component of a viral DNA packaging motor , 2011, Proceedings of the National Academy of Sciences.

[41]  Raymond F. Gesteland,et al.  RNA worlds : from life's origins to diversity in gene regulation , 2011 .

[42]  Stephan H Bernhart,et al.  RNA structure prediction. , 2011, Methods in molecular biology.

[43]  W. Chiu,et al.  Structure of a conserved retroviral RNA packaging element by NMR spectroscopy and cryo-electron tomography. , 2010, Journal of molecular biology.

[44]  D. Turner,et al.  RNA Internal Loops with Tandem AG Pairs: The Structure of the 5′GAGU/3′UGAG Loop Can Be Dramatically Different from Others, Including 5′AAGU/3′UGAA† , 2010, Biochemistry.

[45]  D. Klepacki,et al.  The structure of ribosome-lankacidin complex reveals ribosomal sites for synergistic antibiotics , 2010, Proceedings of the National Academy of Sciences.

[46]  H. Schwalbe,et al.  High-resolution NMR structure of an RNA model system: the 14-mer cUUCGg tetraloop hairpin RNA , 2009, Nucleic acids research.

[47]  J. Šponer,et al.  Molecular Dynamics and Quantum Mechanics of RNA: Conformational and Chemical Change We Can Believe In , 2009, Accounts of chemical research.

[48]  Gabriele Varani,et al.  Simultaneous recognition of HIV-1 TAR RNA bulge and loop sequences by cyclic peptide mimics of Tat protein , 2009, Proceedings of the National Academy of Sciences.

[49]  D. Turner,et al.  Effects of Restrained Sampling Space and Nonplanar Amino Groups on Free-Energy Predictions for RNA with Imino and Sheared Tandem GA Base Pairs Flanked by GC, CG, iGiC or iCiG Base Pairs , 2009, Journal of chemical theory and computation.

[50]  Brent M. Znosko,et al.  Thermodynamic characterization of tandem mismatches found in naturally occurring RNA , 2009, Nucleic acids research.

[51]  Douglas H Turner,et al.  Optical melting measurements of nucleic acid thermodynamics. , 2009, Methods in enzymology.

[52]  M. Gerstein,et al.  RNA-Seq: a revolutionary tool for transcriptomics , 2009, Nature Reviews Genetics.

[53]  A. Serganov,et al.  Structural insights into amino acid binding and gene control by a lysine riboswitch , 2008, Nature.

[54]  P. Bevilacqua,et al.  Structures, kinetics, thermodynamics, and biological functions of RNA hairpins. , 2008, Annual review of physical chemistry.

[55]  Brent M. Znosko,et al.  Thermodynamic characterization of the complete set of sequence symmetric tandem mismatches in RNA and an improved model for predicting the free energy contribution of sequence asymmetric tandem mismatches. , 2008, Biochemistry.

[56]  D. Turner,et al.  NMR reveals the absence of hydrogen bonding in adjacent UU and AG mismatches in an isolated internal loop from ribosomal RNA. , 2007, Biochemistry.

[57]  D. Turner,et al.  NMR structures of (rGCUGAGGCU)2 and (rGCGGAUGCU)2: probing the structural features that shape the thermodynamic stability of GA pairs. , 2007, Biochemistry.

[58]  Ignacio Tinoco,et al.  Unusual mechanical stability of a minimal RNA kissing complex , 2006, Proceedings of the National Academy of Sciences.

[59]  Brent M. Znosko,et al.  Structural features and thermodynamics of the J4/5 loop from the Candida albicans and Candida dubliniensis group I introns. , 2004, Biochemistry.

[60]  D. Turner,et al.  Incorporating chemical modification constraints into a dynamic programming algorithm for prediction of RNA secondary structure. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[61]  Vladim~r%len.  Spin-Echo Water Suppression for the Generation of Pure-Phase Two-Dimensional NMR Spectra , 2004 .

[62]  H. Schwalbe,et al.  NMR Spectroscopy of RNA , 2003, Chembiochem : a European journal of chemical biology.

[63]  Eric Westhof,et al.  The non-Watson-Crick base pairs and their associated isostericity matrices. , 2002, Nucleic acids research.

[64]  D H Turner,et al.  Thermodynamic stabilities of internal loops with GU closing pairs in RNA. , 2001, Biochemistry.

[65]  D H Turner,et al.  Thermodynamics of RNA internal loops with a guanosine-guanosine pair adjacent to another noncanonical pair. , 2001, Biochemistry.

[66]  Vadim V. Demidov,et al.  Nucleic Acids: Structures, Properties and Functions , 2001 .

[67]  I. Tinoco,et al.  A retroviral RNA kissing complex containing only two G.C base pairs. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[68]  J. Doudna,et al.  Ribozyme structures and mechanisms. , 2000, Annual review of biochemistry.

[69]  M J Serra,et al.  A test of the model to predict unusually stable RNA hairpin loop stability. , 2000, RNA.

[70]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[71]  D. Turner,et al.  Thermodynamics of unpaired terminal nucleotides on short RNA helixes correlates with stacking at helix termini in larger RNAs. , 1999, Journal of molecular biology.

[72]  J. Sabina,et al.  Expanded sequence dependence of thermodynamic parameters improves prediction of RNA secondary structure. , 1999, Journal of molecular biology.

[73]  A. Ferré-D’Amaré,et al.  RNA folds: insights from recent crystal structures. , 1999, Annual review of biophysics and biomolecular structure.

[74]  D. Turner,et al.  Thermodynamic parameters for an expanded nearest-neighbor model for formation of RNA duplexes with Watson-Crick base pairs. , 1998, Biochemistry.

[75]  M. Serra,et al.  Stability of RNA hairpins closed by wobble base pairs. , 1998, Biochemistry.

[76]  J. A. Mcdowell,et al.  Thermodynamics of nonsymmetric tandem mismatches adjacent to G.C base pairs in RNA. , 1997, Biochemistry.

[77]  D. Turner,et al.  Solution structure of (rGGCAGGCC)2 by two-dimensional NMR and the iterative relaxation matrix approach. , 1996, Biochemistry.

[78]  D. Turner,et al.  Investigation of the structural basis for thermodynamic stabilities of tandem GU mismatches: solution structure of (rGAGGUCUC)2 by two-dimensional NMR and simulated annealing. , 1996, Biochemistry.

[79]  D Gautheret,et al.  G.U base pairing motifs in ribosomal RNA. , 1995, RNA.

[80]  D. Turner,et al.  A periodic table of symmetric tandem mismatches in RNA. , 1995, Biochemistry.

[81]  A. E. Walter,et al.  The stability and structure of tandem GA mismatches in RNA depend on closing base pairs. , 1994, Biochemistry.

[82]  S. Grzesiek,et al.  The Importance of Not Saturating H2o in Protein NMR : application to Sensitivity Enhancement and Noe Measurements , 1993 .

[83]  D. Turner,et al.  Structure of (rGGCGAGCC)2 in solution from NMR and restrained molecular dynamics. , 1993, Biochemistry.

[84]  Carl R. Woese,et al.  4 Probing RNA Structure, Function, and History by Comparative Analysis , 1993 .

[85]  V. Saudek,et al.  Gradient-tailored excitation for single-quantum NMR spectroscopy of aqueous solutions , 1992, Journal of biomolecular NMR.

[86]  I. Tinoco,et al.  Thermodynamic parameters for loop formation in RNA and DNA hairpin tetraloops. , 1992, Nucleic acids research.

[87]  D. Turner,et al.  Stabilities of consecutive A.C, C.C, G.G, U.C, and U.U mismatches in RNA internal loops: Evidence for stable hydrogen-bonded U.U and C.C.+ pairs. , 1991, Biochemistry.

[88]  D. Turner,et al.  Effects of GA mismatches on the structure and thermodynamics of RNA internal loops. , 1990, Biochemistry.

[89]  C. E. Longfellow,et al.  Thermodynamic and spectroscopic study of bulge loops in oligoribonucleotides. , 1990, Biochemistry.

[90]  Naoki Sugimoto,et al.  Free Energy Increments for Hydrogen Bonds in Nucleic Acid Base Pairs. , 1987 .

[91]  D. Turner,et al.  Improved free-energy parameters for predictions of RNA duplex stability. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[92]  D. Turner,et al.  Stability of XGCGCp, GCGCYp, and XGCGCYp helixes: an empirical estimate of the energetics of hydrogen bonds in nucleic acids. , 1986, Biochemistry.

[93]  D. Turner,et al.  Contributions of dangling end stacking and terminal base-pair formation to the stabilities of XGGCCp, XCCGGp, XGGCCYp, and XCCGGYp helixes. , 1985, Biochemistry.

[94]  Douglas H. Turner,et al.  Effects of 3' dangling end stacking on the stability of GGCC and CCGG double helixes , 1983 .

[95]  C. Lee.  Conformational studies of 13 trinucleoside bisphosphates by 360-MHz 1H-NMR spectroscopy. 1. Ribose protons. , 1983, European journal of biochemistry.

[96]  I. Tinoco,et al.  Conformation studies of 13 trinucleoside diphosphates by 360 MHz PMR spectroscopy. A bulged base conformation. I. Base protons and H1' protons. , 1980, Biophysical chemistry.

[97]  D. Crothers,et al.  Free energy of imperfect nucleic acid helices. 3. Small internal loops resulting from mismatches. , 1973, Journal of molecular biology.

[98]  G. Felsenfeld,et al.  Conformation of polyribouridylic acid in solution. , 1970, Journal of molecular biology.

[99]  J. R. Fresco,et al.  Polynucleotides. VI. Molecular properties and conformation of polyribouridylic acid , 1963 .