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Journal of Bioinformatics and... Aug 2023Most of the functional RNA elements located within large transcripts are local. Local folding therefore serves a practically useful approximation to global structure...
Most of the functional RNA elements located within large transcripts are local. Local folding therefore serves a practically useful approximation to global structure prediction. Due to the sensitivity of RNA secondary structure prediction to the exact definition of sequence ends, accuracy can be increased by averaging local structure predictions over multiple, overlapping sequence windows. These averages can be computed efficiently by dynamic programming. Here we revisit the local folding problem, present a concise mathematical formalization that generalizes previous approaches and show that correct Boltzmann samples can be obtained by local stochastic backtracing in McCaskill's algorithms but not from local folding recursions. Corresponding new features are implemented in the ViennaRNA package to improve the support of local folding. Applications include the computation of maximum expected accuracy structures from RNAplfold data and a mutual information measure to quantify the sensitivity of individual sequence positions.
Topics: RNA Folding; Nucleic Acid Conformation; RNA; Algorithms; RNA, Untranslated
PubMed: 37522173
DOI: 10.1142/S0219720023500166 -
Viruses Oct 2020Viral RNA genomes change shape as virus particles disassemble, form replication complexes, attach to ribosomes for translation, evade host defense mechanisms, and... (Review)
Review
Viral RNA genomes change shape as virus particles disassemble, form replication complexes, attach to ribosomes for translation, evade host defense mechanisms, and assemble new virus particles. These structurally dynamic RNA shapeshifters present a challenging RNA folding problem, because the RNA sequence adopts multiple structures and may sometimes contain regions of partial disorder. Recent advances in high resolution asymmetric cryoelectron microscopy and chemical probing provide new ways to probe the degree of structure and disorder, and have identified more than one conformation in dynamic equilibrium in viral RNA. Chemical probing and the Detection of RNA Folding Ensembles using Expectation Maximization (DREEM) algorithm has been applied to studies of the dynamic equilibrium conformations in HIV RNA in vitro, in virio, and in vivo. This new type of data provides insight into important questions about virus assembly mechanisms and the fundamental physical forces driving virus particle assembly.
Topics: Base Sequence; Cryoelectron Microscopy; Genome, Viral; Nucleic Acid Conformation; RNA Folding; RNA, Viral; Virion; Virus Assembly
PubMed: 33027988
DOI: 10.3390/v12101126 -
PLoS Computational Biology Apr 2022The 3-dimensional fold of an RNA molecule is largely determined by patterns of intramolecular hydrogen bonds between bases. Predicting the base pairing network from the...
The 3-dimensional fold of an RNA molecule is largely determined by patterns of intramolecular hydrogen bonds between bases. Predicting the base pairing network from the sequence, also referred to as RNA secondary structure prediction or RNA folding, is a nondeterministic polynomial-time (NP)-complete computational problem. The structure of the molecule is strongly predictive of its functions and biochemical properties, and therefore the ability to accurately predict the structure is a crucial tool for biochemists. Many methods have been proposed to efficiently sample possible secondary structure patterns. Classic approaches employ dynamic programming, and recent studies have explored approaches inspired by evolutionary and machine learning algorithms. This work demonstrates leveraging quantum computing hardware to predict the secondary structure of RNA. A Hamiltonian written in the form of a Binary Quadratic Model (BQM) is derived to drive the system toward maximizing the number of consecutive base pairs while jointly maximizing the average length of the stems. A Quantum Annealer (QA) is compared to a Replica Exchange Monte Carlo (REMC) algorithm programmed with the same objective function, with the QA being shown to be highly competitive at rapidly identifying low energy solutions. The method proposed in this study was compared to three algorithms from literature and, despite its simplicity, was found to be competitive on a test set containing known structures with pseudoknots.
Topics: Algorithms; Computational Biology; Computers; Computing Methodologies; Nucleic Acid Conformation; Quantum Theory; RNA; RNA Folding
PubMed: 35404931
DOI: 10.1371/journal.pcbi.1010032 -
Journal of Physics. Condensed Matter :... Jun 2015RNA molecules are essential cellular machines performing a wide variety of functions for which a specific three-dimensional structure is required. Over the last several... (Review)
Review
RNA molecules are essential cellular machines performing a wide variety of functions for which a specific three-dimensional structure is required. Over the last several years, the experimental determination of RNA structures through x-ray crystallography and NMR seems to have reached a plateau in the number of structures resolved each year, but as more and more RNA sequences are being discovered, the need for structure prediction tools to complement experimental data is strong. Theoretical approaches to RNA folding have been developed since the late nineties, when the first algorithms for secondary structure prediction appeared. Over the last 10 years a number of prediction methods for 3D structures have been developed, first based on bioinformatics and data-mining, and more recently based on a coarse-grained physical representation of the systems. In this review we are going to present the challenges of RNA structure prediction and the main ideas behind bioinformatic approaches and physics-based approaches. We will focus on the description of the more recent physics-based phenomenological models and on how they are built to include the specificity of the interactions of RNA bases, whose role is critical in folding. Through examples from different models, we will point out the strengths of physics-based approaches, which are able not only to predict equilibrium structures, but also to investigate dynamical and thermodynamical behavior, and the open challenges to include more key interactions ruling RNA folding.
Topics: Computational Biology; Models, Molecular; Nucleic Acid Conformation; RNA; RNA Folding
PubMed: 25993396
DOI: 10.1088/0953-8984/27/23/233102 -
Cold Spring Harbor Perspectives in... Oct 2018The past decades have witnessed tremendous developments in our understanding of RNA biology. At the core of these advances have been studies aimed at discerning RNA... (Review)
Review
The past decades have witnessed tremendous developments in our understanding of RNA biology. At the core of these advances have been studies aimed at discerning RNA structure and at understanding the forces that influence the RNA folding process. It is easy to take the present state of understanding for granted, but there is much to be learned by considering the path to our current understanding, which has been tortuous, with the birth and death of models, the adaptation of experimental tools originally developed for characterization of protein structure and catalysis, and the development of novel tools for probing RNA. In this review we tour the stages of RNA folding studies, considering them as "epochs" that can be generalized across scientific disciplines. These epochs span from the discovery of catalytic RNA, through biophysical insights into the putative primordial RNA World, to characterization of structured RNAs, the building and testing of models, and, finally, to the development of models with the potential to yield generalizable predictive and quantitative models for RNA conformational, thermodynamic, and kinetic behavior. We hope that this accounting will aid others as they navigate the many fascinating questions about RNA and its roles in biology, in the past, present, and future.
Topics: Animals; Humans; Models, Chemical; RNA; RNA Folding; Thermodynamics
PubMed: 30275276
DOI: 10.1101/cshperspect.a032433 -
Journal of Biotechnology Nov 2017In the realm of nucleic acid structures, secondary structure forms a conceptually important intermediate level of description and explains the dominating part of the... (Review)
Review
In the realm of nucleic acid structures, secondary structure forms a conceptually important intermediate level of description and explains the dominating part of the free energy of structure formation. Secondary structures are well conserved over evolutionary time-scales and for many classes of RNAs evolve slower than the underlying primary sequences. Given the close link between structure and function, secondary structure is routinely used as a basis to explain experimental findings. Recent technological advances, finally, have made it possible to assay secondary structure directly using high throughput methods. From a computational biology point of view, secondary structures have a special role because they can be computed efficiently using exact dynamic programming algorithms. In this contribution we provide a short overview of RNA folding algorithms, recent additions and variations and address methods to align, compare, and cluster RNA structures, followed by a tabular summary of the most important software suites in the fields.
Topics: Algorithms; Computational Biology; Nucleic Acid Conformation; RNA; RNA Folding; Sequence Analysis, RNA; Software
PubMed: 28690134
DOI: 10.1016/j.jbiotec.2017.07.007 -
Nature Communications Jan 2023Guanine (G)-rich nucleic acids can fold into G-quadruplex (G4) structures under permissive conditions. Although many RNAs contain sequences that fold into RNA G4s (rG4s)...
Guanine (G)-rich nucleic acids can fold into G-quadruplex (G4) structures under permissive conditions. Although many RNAs contain sequences that fold into RNA G4s (rG4s) in vitro, their folding and functions in vivo are not well understood. In this report, we showed that the folding of putative rG4s in human cells into rG4 structures is dynamically regulated under stress. By using high-throughput dimethylsulfate (DMS) probing, we identified hundreds of endogenous stress-induced rG4s, and validated them by using an rG4 pull-down approach. Our results demonstrate that stress-induced rG4s are enriched in mRNA 3'-untranslated regions and enhance mRNA stability. Furthermore, stress-induced rG4 folding is readily reversible upon stress removal. In summary, our study revealed the dynamic regulation of rG4 folding in human cells and suggested that widespread rG4 motifs may have a global regulatory impact on mRNA stability and cellular stress response.
Topics: Humans; RNA; RNA, Messenger; G-Quadruplexes; RNA Folding; RNA Stability
PubMed: 36639366
DOI: 10.1038/s41467-023-35811-x -
Interdisciplinary Sciences,... Sep 2023RNA folding prediction is very meaningful and challenging. The molecular dynamics simulation (MDS) of all atoms (AA) is limited to the folding of small RNA molecules. At...
RNA folding prediction is very meaningful and challenging. The molecular dynamics simulation (MDS) of all atoms (AA) is limited to the folding of small RNA molecules. At present, most of the practical models are coarse grained (CG) model, and the coarse-grained force field (CGFF) parameters usually depend on known RNA structures. However, the limitation of the CGFF is obvious that it is difficult to study the modified RNA. Based on the 3 beads model (AIMS_RNA_B3), we proposed the AIMS_RNA_B5 model with three beads representing a base and two beads representing the main chain (sugar group and phosphate group). We first run the all atom molecular dynamic simulation (AAMDS), and fit the CGFF parameter with the AA trajectory. Then perform the coarse-grained molecular dynamic simulation (CGMDS). AAMDS is the foundation of CGMDS. CGMDS is mainly to carry out the conformation sampling based on the current AAMDS state and improve the folding speed. We simulated the folding of three RNAs, which belong to hairpin, pseudoknot and tRNA respectively. Compared to the AIMS_RNA_B3 model, the AIMS_RNA_B5 model is more reasonable and performs better.
Topics: RNA Folding; Molecular Dynamics Simulation; RNA
PubMed: 37115389
DOI: 10.1007/s12539-023-00561-3 -
BioEssays : News and Reviews in... Aug 2022Construction of the eukaryotic ribosome is a complex process in which a nascent ribosomal RNA (rRNA) emerging from RNA Polymerase I hierarchically folds into a native...
Construction of the eukaryotic ribosome is a complex process in which a nascent ribosomal RNA (rRNA) emerging from RNA Polymerase I hierarchically folds into a native three-dimensional structure. Modular assembly of individual RNA domains through interactions with ribosomal proteins and a myriad of assembly factors permit efficient disentanglement of the error-prone RNA folding process. Following these dynamic events, long-range tertiary interactions are orchestrated to compact rRNA. A combination of genetic, biochemical, and structural studies is now providing clues into how a nascent rRNA is transformed into a functional ribosome with high precision. With this essay, we aim to draw attention to the poorly understood process of establishing correct RNA tertiary contacts during ribosome formation.
Topics: RNA Folding; RNA, Ribosomal; Ribosomal Proteins; Ribosomes
PubMed: 35751450
DOI: 10.1002/bies.202200066 -
Proceedings of the National Academy of... Jun 2023A synthetic biology approach toward constructing an RNA-based genome expands our understanding of living things and opens avenues for technological advancement. For the...
A synthetic biology approach toward constructing an RNA-based genome expands our understanding of living things and opens avenues for technological advancement. For the precise design of an artificial RNA replicon either from scratch or based on a natural RNA replicon, understanding structure-function relationships of RNA sequences is critical. However, our knowledge remains limited to a few particular structural elements intensively studied so far. Here, we conducted a series of site-directed mutagenesis studies of yeast narnaviruses ScNV20S and ScNV23S, perhaps the simplest natural autonomous RNA replicons, to identify RNA elements required for maintenance and replication. RNA structure disruption corresponding to various portions of the entire narnavirus genome suggests that pervasive RNA folding, in addition to the precise secondary structure of genome termini, is essential for maintenance of the RNA replicon in vivo. Computational RNA structure analyses suggest that this scenario likely applies to other "narna-like" viruses. This finding implies selective pressure on these simplest autonomous natural RNA replicons to fold into a unique structure that acquires both thermodynamic and biological stability. We propose the importance of pervasive RNA folding for the design of RNA replicons that could serve as a platform for in vivo continuous evolution as well as an interesting model to study the origin of life.
Topics: RNA, Viral; RNA Folding; Genome, Viral; RNA Viruses; Base Sequence; Replicon; Virus Replication
PubMed: 37339222
DOI: 10.1073/pnas.2304082120