Constraint counting on RNA structures: linking flexibility and function.

RNA structures are highly flexible biomolecules that can undergo dramatic conformational changes required to fulfill their diverse functional roles. Constraint counting on a topological network representation of an RNA structure can provide very efficiently detailed insights into the intrinsic flexibility characteristics of the biomolecule. In the network, vertices represent atoms and edges represent covalent and strong non-covalent bonds and angle constraints. Initially, the method has been successfully applied to identify rigid and flexible regions in proteins. Here, we present recent progress in extending the approach to RNA structures. As a case study, we analyze stability characteristics of the ribosomal exit tunnel and relate these findings to the tunnel's active role in co-translational processes.

[1]  J. Frank,et al.  Dynamic reorganization of the functionally active ribosome explored by normal mode analysis and cryo-electron microscopy , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[2]  D. Patel,et al.  Concerted motions in HIV-1 TAR RNA may allow access to bound state conformations: RNA dynamics from NMR residual dipolar couplings. , 2002, Journal of molecular biology.

[3]  F. Hartl,et al.  The dynamic tunnel , 2004, Nature Structural &Molecular Biology.

[4]  Joanna Trylska,et al.  Exploring global motions and correlations in the ribosome. , 2005, Biophysical journal.

[5]  R. Jernigan,et al.  Anisotropy of fluctuation dynamics of proteins with an elastic network model. , 2001, Biophysical journal.

[6]  H. Gohlke,et al.  Exploiting the Link between Protein Rigidity and Thermostability for Data‐Driven Protein Engineering , 2008 .

[7]  Peter J McCormick,et al.  Nascent Membrane and Secretory Proteins Differ in FRET-Detected Folding Far inside the Ribosome and in Their Exposure to Ribosomal Proteins , 2004, Cell.

[8]  Nils G Walter,et al.  Molecular dynamics simulations of RNA: an in silico single molecule approach. , 2007, Biopolymers.

[9]  D. Case,et al.  Multiscale modeling of nucleic acids: Insights into DNA flexibility , 2008, Biopolymers.

[10]  Holger Gohlke,et al.  Change in protein flexibility upon complex formation: Analysis of Ras‐Raf using molecular dynamics and a molecular framework approach , 2004, Proteins.

[11]  A. Bashan,et al.  Ribosomal antibiotics: structural basis for resistance, synergism and selectivity. , 2004, Trends in biotechnology.

[12]  Dennis R Livesay,et al.  Conserved quantitative stability/flexibility relationships (QSFR) in an orthologous RNase H pair , 2005, Proteins.

[13]  G. Giacomello,et al.  Proteins structure. , 1957, Scientia medica italica. English ed.

[14]  R. Jernigan,et al.  Global ribosome motions revealed with elastic network model. , 2004, Journal of structural biology.

[15]  Gerhard Stock,et al.  Conformational dynamics of RNA-peptide binding: a molecular dynamics simulation study. , 2006, Biophysical journal.

[16]  H. Al‐Hashimi,et al.  RNA dynamics: it is about time. , 2008, Current opinion in structural biology.

[17]  Ioan Andricioaei,et al.  iRED analysis of TAR RNA reveals motional coupling, long-range correlations, and a dynamical hinge. , 2007, Biophysical journal.

[18]  Koreaki Ito,et al.  The Ribosomal Exit Tunnel Functions as a Discriminating Gate , 2002, Cell.

[19]  Frank Schluenzen,et al.  Structural insight into the role of the ribosomal tunnel in cellular regulation , 2003, Nature Structural Biology.

[20]  David E Draper,et al.  A guide to ions and RNA structure. , 2004, RNA.

[21]  R. Jernigan,et al.  Collective dynamics of the ribosomal tunnel revealed by elastic network modeling , 2009, Proteins.

[22]  Thomas A Steitz,et al.  The structural basis of large ribosomal subunit function. , 2002, Annual review of biochemistry.

[23]  R. Garrett,et al.  Chloramphenicol resistance mutations in the single 23S rRNA gene of the archaeon Halobacterium halobium , 1991, Journal of bacteriology.

[24]  Holger Gohlke,et al.  A natural coarse graining for simulating large biomolecular motion. , 2006, Biophysical journal.

[25]  A. Rader,et al.  Identifying protein folding cores from the evolution of flexible regions during unfolding. , 2002, Journal of molecular graphics & modelling.

[26]  Philippe Dumas,et al.  Detailed analysis of RNA-protein interactions within the bacterial ribosomal protein L5/5S rRNA complex. , 2002, RNA.

[27]  F. J. Luque,et al.  The relative flexibility of B-DNA and A-RNA duplexes: database analysis. , 2004, Nucleic acids research.

[28]  Gregor Blaha,et al.  Mutations outside the anisomycin-binding site can make ribosomes drug-resistant. , 2008, Journal of molecular biology.

[29]  Qi Zhang,et al.  Resolving the Motional Modes That Code for RNA Adaptation , 2006, Science.

[30]  Joachim Frank,et al.  Ribosome dynamics: insights from atomic structure modeling into cryo-electron microscopy maps. , 2006, Annual review of biophysics and biomolecular structure.

[31]  R. Ornstein,et al.  An optimized potential function for the calculation of nucleic acid interaction energies I. Base stacking , 1978, Biopolymers.

[32]  T. Steitz,et al.  The structural basis of ribosome activity in peptide bond synthesis. , 2000, Science.

[33]  M. Thorpe,et al.  Constrained geometric simulation of diffusive motion in proteins , 2005, Physical biology.

[34]  A. Atilgan,et al.  Direct evaluation of thermal fluctuations in proteins using a single-parameter harmonic potential. , 1997, Folding & design.

[35]  L. Landweber,et al.  RNA editing missing in mitochondria. , 1997, RNA.

[36]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[37]  H. Gohlke,et al.  Multiscale modeling of macromolecular conformational changes combining concepts from rigidity and elastic network theory , 2006, Proteins.

[38]  T. Steitz,et al.  The complete atomic structure of the large ribosomal subunit at 2.4 A resolution. , 2000, Science.

[39]  Thomas A Steitz,et al.  Structures of five antibiotics bound at the peptidyl transferase center of the large ribosomal subunit. , 2003, Journal of molecular biology.

[40]  Donald J. Jacobs,et al.  Generic rigidity in three-dimensional bond-bending networks , 1998 .

[41]  I. Bahar,et al.  Folding core predictions from network models of proteins , 2004 .

[42]  B. Hendrickson,et al.  Regular ArticleAn Algorithm for Two-Dimensional Rigidity Percolation: The Pebble Game , 1997 .

[43]  M Gerstein,et al.  The geometry of the ribosomal polypeptide exit tunnel. , 2006, Journal of molecular biology.

[44]  E Westhof,et al.  A molecular dynamics simulation study of an aminoglycoside/A-site RNA complex: conformational and hydration patterns. , 2006, Biochimie.

[45]  Joachim Frank,et al.  Elongation arrest by SecM via a cascade of ribosomal RNA rearrangements. , 2006, Molecular cell.

[46]  D. Jacobs,et al.  Protein flexibility predictions using graph theory , 2001, Proteins.

[47]  Changbong Hyeon,et al.  Size, shape, and flexibility of RNA structures. , 2006, The Journal of chemical physics.

[48]  Holger Gohlke,et al.  Statics of the ribosomal exit tunnel: implications for cotranslational peptide folding, elongation regulation, and antibiotics binding. , 2009, Journal of molecular biology.

[49]  J. Puglisi,et al.  Conformation of the TAR RNA-arginine complex by NMR spectroscopy. , 1992, Science.

[50]  Hassan A. Karimi,et al.  oGNM: online computation of structural dynamics using the Gaussian Network Model , 2006, Nucleic Acids Res..

[51]  M. Ehrenberg,et al.  Regulatory Nascent Peptides in the Ribosomal Tunnel , 2002, Cell.

[52]  Adam W Van Wynsberghe,et al.  Comparison of mode analyses at different resolutions applied to nucleic acid systems. , 2005, Biophysical journal.

[53]  Stephen Neidle,et al.  Principles of nucleic acid structure , 2007 .

[54]  C. Dobson,et al.  Three-dimensional structures of translating ribosomes by Cryo-EM. , 2004, Molecular cell.

[55]  J. Berg,et al.  Molecular dynamics simulations of biomolecules , 2002, Nature Structural Biology.

[56]  R L Jernigan,et al.  Vibrational dynamics of transfer RNAs: comparison of the free and synthetase-bound forms. , 1998, Journal of molecular biology.

[57]  Jianli Lu,et al.  Folding zones inside the ribosomal exit tunnel , 2005, Nature Structural &Molecular Biology.

[58]  Holger Gohlke,et al.  Analyzing the flexibility of RNA structures by constraint counting. , 2008, Biophysical journal.

[59]  Yael Mandel-Gutfreund,et al.  Revealing unique properties of the ribosome using a network based analysis , 2008, Nucleic acids research.

[60]  John B. Shoven,et al.  I , Edinburgh Medical and Surgical Journal.

[61]  H. Bernstein,et al.  Translation arrest requires two-way communication between a nascent polypeptide and the ribosome. , 2006, Molecular cell.

[62]  J. Puglisi,et al.  Paromomycin binding induces a local conformational change in the A-site of 16 S rRNA. , 1998, Journal of molecular biology.

[63]  Miss A.O. Penney.  (b) , 1974, The New Yale Book of Quotations.

[64]  Hashim M. Al-Hashimi,et al.  Review NMR studies of RNA dynamics and structural plasticity using NMR residual dipolar couplings , 2007 .

[65]  E Westhof,et al.  Water and ion binding around RNA and DNA (C,G) oligomers. , 2000, Journal of molecular biology.

[66]  P A Kollman,et al.  Molecular dynamics studies of the HIV-1 TAR and its complex with argininamide. , 2000, Nucleic acids research.

[67]  Poul Nissen,et al.  The structures of four macrolide antibiotics bound to the large ribosomal subunit. , 2002, Molecular cell.

[68]  P. Auffinger,et al.  Nucleic acid solvation: from outside to insight. , 2007, Current opinion in structural biology.

[69]  Modesto Orozco,et al.  Recent advances in the study of nucleic acid flexibility by molecular dynamics. , 2008, Current opinion in structural biology.

[70]  A. Bashan,et al.  Ribosomal crystallography: initiation, peptide bond formation, and amino acid polymerization are hampered by antibiotics. , 2004, Annual review of microbiology.

[71]  Ivet Bahar,et al.  Anisotropic network model: systematic evaluation and a new web interface , 2006, Bioinform..

[72]  Joachim Frank,et al.  A ratchet-like inter-subunit reorganization of the ribosome during translocation , 2000, Nature.

[73]  Leslie A Kuhn,et al.  Protein unfolding: Rigidity lost , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[74]  E Westhof,et al.  Molecular dynamics simulations of solvated yeast tRNA(Asp). , 1999, Biophysical journal.

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

[76]  R. Amils,et al.  Functional analysis of seven ribosomal systems from extremely halophilic archaea , 1993 .

[77]  B. Hendrickson,et al.  An Algorithm for Two-Dimensional Rigidity Percolation , 1997 .