Secondary structural entropy in RNA switch (Riboswitch) identification

Manzourolajdad, Amirhossein; Arnold, Jonathan

doi:10.1186/s12859-015-0523-2

Cited by 16 publications

(7 citation statements)

References 132 publications

(131 reference statements)

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“…Many riboswitches, such as the guanine-responsive riboswitch from the xpt-pbuX operon of Bacillus subtilis (49) and the thiamine-pyrophosphate-specific riboswitch of Arabidopsis thaliana (50), make use of a three-way junction architecture to form their aptamer domain. When the aptamer binds its target ligand, additional constraints arising from the reconfiguration of the binding pocket either destabilize existing tertiary interactions or stabilize additional tertiary contacts, leading to a rearrangement of the folded structure and causing an upstream or downstream switching sequence to rehybridize and produce a global shape transformation in the riboswitch RNA (51, 52, 53). Fig.…”

Section: Discussionmentioning

confidence: 99%

Topological Constraints and Their Conformational Entropic Penalties on RNA Folds

Mak

Phan

2018

Biophysical Journal

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Functional RNAs can fold into intricate structures using a number of different secondary and tertiary structural motifs. Many factors contribute to the overall free energy of the target fold. This study aims at quantifying the entropic costs coming from the loss of conformational freedom when the sugar-phosphate backbone is subjected to constraints imposed by secondary and tertiary contacts. Motivated by insights from topology theory, we design a diagrammatic scheme to represent different types of RNA structures so that constraints associated with a folded structure may be segregated into mutually independent subsets, enabling the total conformational entropy loss to be easily calculated as a sum of independent terms. We used high-throughput Monte Carlo simulations to simulate large ensembles of single-stranded RNA sequences in solution to validate the assumptions behind our diagrammatic scheme, examining the entropic costs for hairpin initiation and formation of many multiway junctions. Our diagrammatic scheme aids in the factorization of secondary/tertiary constraints into distinct topological classes and facilitates the discovery of interrelationships among multiple constraints on RNA folds. This perspective, which to our knowledge is novel, leads to useful insights into the inner workings of some functional RNA sequences, demonstrating how they might operate by transforming their structures among different topological classes.

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Section: Discussionmentioning

confidence: 99%

Topological Constraints and Their Conformational Entropic Penalties on RNA Folds

Mak

Phan

2018

Biophysical Journal

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“…Therefore, the properties of RNA secondary structure neutral networks do not only permit the contact (separated by one mutation) between almost any two secondary structures; these networks overlap sufficiently so as to yield any two different folded structures with one genotype. Natural selection has taken advantage of the plasticity of the RNA genotype in the design of RNA switches [ 47 ] or in a case where a sequence is reused to eventually perform three different catalytic roles in vivo [ 48 ].…”

Section: Elements Of Adaptive Multiscapesmentioning

confidence: 99%

Adaptive multiscapes: an up-to-date metaphor to visualize molecular adaptation

Catalán

Arias²,

Cuesta

et al. 2017

Biol Direct

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BackgroundWright’s metaphor of the fitness landscape has shaped and conditioned our view of the adaptation of populations for almost a century. Since its inception, and including criticism raised by Wright himself, the concept has been surrounded by controversy. Among others, the debate stems from the intrinsic difficulty to capture important features of the space of genotypes, such as its high dimensionality or the existence of abundant ridges, in a visually appealing two-dimensional picture. Two additional currently widespread observations come to further constrain the applicability of the original metaphor: the very skewed distribution of phenotype sizes (which may actively prevent, due to entropic effects, the achievement of fitness maxima), and functional promiscuity (i.e. the existence of secondary functions which entail partial adaptation to environments never encountered before by the population).ResultsHere we revise some of the shortcomings of the fitness landscape metaphor and propose a new “scape” formed by interconnected layers, each layer containing the phenotypes viable in a given environment. Different phenotypes within a layer are accessible through mutations with selective value, while neutral mutations cause displacements of populations within a phenotype. A different environment is represented as a separated layer, where phenotypes may have new fitness values, other phenotypes may be viable, and the same genotype may yield a different phenotype, representing genotypic promiscuity. This scenario explicitly includes the many-to-many structure of the genotype-to-phenotype map. A number of empirical observations regarding the adaptation of populations in the light of adaptive multiscapes are reviewed.ConclusionsSeveral shortcomings of Wright’s visualization of fitness landscapes can be overcome through adaptive multiscapes. Relevant aspects of population adaptation, such as neutral drift, functional promiscuity or environment-dependent fitness, as well as entropic trapping and the concomitant impossibility to reach fitness peaks are visualized at once. Adaptive multiscapes should aid in the qualitative understanding of the multiple pathways involved in evolutionary dynamics.ReviewersThis article was reviewed by Eugene Koonin and Ricard Solé.

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“…Such approaches perform well when the riboregulator is highly conserved between distant organisms, but are expected to miss RNA elements that are rare or evolutionarily diverged ( 9 , 13 ). Several tools use thermodynamics-based methods to search for RNA elements that can adopt alternative conformations ( 14 – 17 ), but these methods are not specifically directed towards finding features of conditional terminators, and may be less effective in detecting riboswitches in which one of the conformations is only stable when bound to the ligand ( 18 ). To our knowledge there is currently no tool that utilizes the basic concept of mutually exclusive terminator-antiterminator conformations in order to predict riboregulators that function via regulated termination.…”

Section: Introductionmentioning

confidence: 99%

Computational prediction of regulatory, premature transcription termination in bacteria

Millman¹,

Dar²,

Shamir³

et al. 2016

Nucleic Acids Res

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A common strategy for regulation of gene expression in bacteria is conditional transcription termination. This strategy is frequently employed by 5′UTR cis-acting RNA elements (riboregulators), including riboswitches and attenuators. Such riboregulators can assume two mutually exclusive RNA structures, one of which forms a transcriptional terminator and results in premature termination, and the other forms an antiterminator that allows read-through into the coding sequence to produce a full-length mRNA. We developed a machine-learning based approach, which, given a 5′UTR of a gene, predicts whether it can form the two alternative structures typical to riboregulators employing conditional termination. Using a large positive training set of riboregulators derived from 89 human microbiome bacteria, we show high specificity and sensitivity for our classifier. We further show that our approach allows the discovery of previously unidentified riboregulators, as exemplified by the detection of new LeuA leaders and T-boxes in Streptococci. Finally, we developed PASIFIC (www.weizmann.ac.il/molgen/Sorek/PASIFIC/), an online web-server that, given a user-provided 5′UTR sequence, predicts whether this sequence can adopt two alternative structures conforming with the conditional termination paradigm. This webserver is expected to assist in the identification of new riboswitches and attenuators in the bacterial pan-genome.

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Secondary structural entropy in RNA switch (Riboswitch) identification

Cited by 16 publications

References 132 publications

Topological Constraints and Their Conformational Entropic Penalties on RNA Folds

Topological Constraints and Their Conformational Entropic Penalties on RNA Folds

Adaptive multiscapes: an up-to-date metaphor to visualize molecular adaptation

Computational prediction of regulatory, premature transcription termination in bacteria

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