Graphical exploratory data analysis of RNA secondary structure dynamics predicted by the massively parallel genetic algorithm.

Studies indicate that RNA may enter intermediate and multiple conformational states, which may impact gene expression and molecular function. It is known that the biologically functional states of RNA molecules may not correspond to their minimum energy conformations, that kinetic barriers may trap the molecule in a local minimum, that folding often occurs during transcription, and that cases exist in which a molecule will transition between one or more functional conformations. Thus, methods for simulating the folding pathway and dynamic behavior of an RNA molecule are important for the prediction of RNA structure and its associated functions. We have developed several data mining techniques guided by interactive visualization tools associated with our massively parallel genetic algorithm for RNA/DNA secondary structure prediction, MPGAfold, and StructureLab analysis workbench. Most of the methods and tools are also applicable to dynamic programming algorithm (DPA) folding data analysis. When applied to MPGAfold results these methodologies are used to determine the significant intermediate and final structures associated with co-transcriptional and full length RNA folding. Since the genetic algorithm is essentially stochastic, multiple runs are required to develop a consensus understanding of an RNA structure. The interactive visualizations facilitate interpretation of results from sequential or full length individual MPGAfold runs, final results of multiple folding runs, including multiple population sizes, and the results from multiple RNA sequences of one family. This paper describes several of these techniques and shows how they are used to help solve this highly combinatoric problem.

[1]  Walter Fontana,et al.  Fast folding and comparison of RNA secondary structures , 1994 .

[2]  Bruce A. Shapiro,et al.  A massively parallel genetic algorithm for RNA secondary structure prediction , 1994, The Journal of Supercomputing.

[3]  B. Shapiro,et al.  RNA secondary structure prediction from sequence alignments using a network of k-nearest neighbor classifiers. , 2006, RNA.

[4]  Bruce A. Shapiro,et al.  Structural polymorphism of the HIV-1 leader region explored by computational methods , 2005, Nucleic acids research.

[5]  Ben Berkhout,et al.  Multiple secondary structure rearrangements during HIV-1 RNA dimerization. , 2002, Biochemistry.

[6]  Bruce A. Shapiro,et al.  Stem Trace: an interactive visual tool for comparative RNA structure analysis , 1999, Bioinform..

[7]  Niles A. Pierce,et al.  A partition function algorithm for nucleic acid secondary structure including pseudoknots , 2003, J. Comput. Chem..

[8]  R A Sayle,et al.  RASMOL: biomolecular graphics for all. , 1995, Trends in biochemical sciences.

[9]  Kaizhong Zhang,et al.  Comparing multiple RNA secondary structures using tree comparisons , 1990, Comput. Appl. Biosci..

[10]  D. Turner,et al.  Improved predictions of secondary structures for RNA. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[11]  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.

[12]  C. Guthrie,et al.  Mechanical Devices of the Spliceosome: Motors, Clocks, Springs, and Things , 1998, Cell.

[13]  J. Maizel,et al.  Enhanced graphic matrix analysis of nucleic acid and protein sequences. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[14]  Alain Xayaphoummine,et al.  Kinefold web server for RNA/DNA folding path and structure prediction including pseudoknots and knots , 2005, Nucleic Acids Res..

[15]  Jin Chu Wu,et al.  The massively parallel genetic algorithm for RNA folding: MIMD implementation and population variation , 2001, Bioinform..

[16]  Bruce A Shapiro,et al.  The prediction of the wild-type telomerase RNA pseudoknot structure and the pivotal role of the bulge in its formation. , 2006, Journal of molecular graphics & modelling.

[17]  D. Turner,et al.  Predicting optimal and suboptimal secondary structure for RNA. , 1990, Methods in enzymology.

[18]  Daniel Gautheret,et al.  An RNA pattern matching program with enhanced performance and portability , 1994, Comput. Appl. Biosci..

[19]  Roland Marquet,et al.  Dimerization of retroviral RNA genomes: an inseparable pair , 2004, Nature Reviews Microbiology.

[20]  Ben Berkhout,et al.  In Vitro Evidence That the Untranslated Leader of the HIV-1 Genome Is an RNA Checkpoint That Regulates Multiple Functions through Conformational Changes* , 2002, The Journal of Biological Chemistry.

[21]  Ivo L. Hofacker,et al.  Vienna RNA secondary structure server , 2003, Nucleic Acids Res..

[22]  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.

[23]  I M Verma,et al.  Optical absorbance properties of mitochondrial ribosomal RNA. , 1971, Biochemical and biophysical research communications.

[24]  J. C. Wu,et al.  RNA folding pathway functional intermediates: their prediction and analysis. , 2001, Journal of molecular biology.

[25]  Weixiong Zhang,et al.  ILM: a web server for predicting RNA secondary structures with pseudoknots , 2004, Nucleic Acids Res..

[26]  E. Siggia,et al.  Modeling RNA folding paths with pseudoknots: application to hepatitis delta virus ribozyme. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[27]  E. Nudler,et al.  The riboswitch control of bacterial metabolism. , 2004, Trends in biochemical sciences.

[28]  K. Weeks,et al.  RNA structure analysis at single nucleotide resolution by selective 2'-hydroxyl acylation and primer extension (SHAPE). , 2005, Journal of the American Chemical Society.

[29]  Jin Chu Wu,et al.  Predicting RNA H-type pseudoknots with the massively parallel genetic algorithm , 1997, Comput. Appl. Biosci..

[30]  Bruce A. Shapiro,et al.  An algorithm for comparing multiple RNA secondary structures , 1988, Comput. Appl. Biosci..

[31]  Bjarne Knudsen,et al.  Pfold: RNA Secondary Structure Prediction Using Stochastic Context-Free Grammars , 2003 .

[32]  M. Zuker.  On finding all suboptimal foldings of an RNA molecule. , 1989, Science.

[33]  Bjarne Knudsen,et al.  RNA secondary structure prediction using stochastic context-free grammars and evolutionary history , 1999, Bioinform..

[34]  A. E. Walter,et al.  Coaxial stacking of helixes enhances binding of oligoribonucleotides and improves predictions of RNA folding. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[35]  D. Turner,et al.  RNA structure prediction. , 1988, Annual review of biophysics and biophysical chemistry.

[36]  John H. Holland,et al.  Adaptation in Natural and Artificial Systems: An Introductory Analysis with Applications to Biology, Control, and Artificial Intelligence , 1992 .

[37]  Robert Giegerich,et al.  RNAshapes: an integrated RNA analysis package based on abstract shapes. , 2006, Bioinformatics.

[38]  H. Huthoff,et al.  Two alternating structures of the HIV-1 leader RNA. , 2001, RNA.

[39]  Wojciech Kasprzak,et al.  Structural Differentiation of the HIV-1 Poly(A) Signals , 2006, Journal of biomolecular structure & dynamics.

[40]  Jin Chu Wu,et al.  An annealing mutation operator in the genetic algorithms for RNA folding , 1996, Comput. Appl. Biosci..

[41]  D. Giedroc,et al.  Structure, stability and function of RNA pseudoknots involved in stimulating ribosomal frameshifting1 , 2000, Journal of Molecular Biology.

[42]  Ye Ding,et al.  Structure clustering features on the Sfold Web server , 2005, Bioinform..

[43]  Roger A. Sayle,et al.  RasMol v2.4 A Molecular Visualisation Program , 1994 .

[44]  R. Giegerich,et al.  Complete probabilistic analysis of RNA shapes , 2006, BMC Biology.

[45]  B A Shapiro,et al.  STRUCTURELAB: a heterogeneous bioinformatics system for RNA structure analysis. , 1996, Journal of molecular graphics.

[46]  Robert Giegerich,et al.  Design, implementation and evaluation of a practical pseudoknot folding algorithm based on thermodynamics , 2004, BMC Bioinformatics.

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

[48]  P. Stadler,et al.  Secondary structure prediction for aligned RNA sequences. , 2002, Journal of molecular biology.

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

[50]  B A Shapiro,et al.  A Boltzmann filter improves the prediction of RNA folding pathways in a massively parallel genetic algorithm. , 1999, Journal of biomolecular structure & dynamics.

[51]  H. Noller.  Structure of ribosomal RNA. , 1984, Annual review of biochemistry.

[52]  J. Gorodkin,et al.  RNA interactions in the 5' region of the HIV-1 genome. , 2004, Journal of molecular biology.

[53]  Karen S Lavery,et al.  Antisense and RNAi: powerful tools in drug target discovery and validation. , 2003, Current opinion in drug discovery & development.

[54]  John H. Holland,et al.  Adaptation in Natural and Artificial Systems: An Introductory Analysis with Applications to Biology, Control, and Artificial Intelligence , 1992 .

[55]  C. Lawrence,et al.  RNA secondary structure prediction by centroids in a Boltzmann weighted ensemble. , 2005, RNA.

[56]  E Rivas,et al.  A dynamic programming algorithm for RNA structure prediction including pseudoknots. , 1998, Journal of molecular biology.

[57]  David E. Goldberg,et al.  Genetic Algorithms in Search Optimization and Machine Learning , 1988 .

[58]  Weixiong Zhang,et al.  An Iterated loop matching approach to the prediction of RNA secondary structures with pseudoknots , 2004, Bioinform..

[59]  Holger Gohlke,et al.  The Amber biomolecular simulation programs , 2005, J. Comput. Chem..

[60]  H. Hoos,et al.  HotKnots: heuristic prediction of RNA secondary structures including pseudoknots. , 2005, RNA.

[61]  Kevin M Weeks,et al.  RNA SHAPE chemistry reveals nonhierarchical interactions dominate equilibrium structural transitions in tRNA(Asp) transcripts. , 2005, Journal of the American Chemical Society.

[62]  Robert Giegerich,et al.  Abstract shapes of RNA. , 2004, Nucleic acids research.

[63]  D Riesner,et al.  Temperature‐Gradient gel electrophoresis of nucleic acids: Analysis of conformational transitions, sequence variations, and protein‐nucleic acid interactions , 1989, Electrophoresis.