Fast, approximate kinetics of RNA folding

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Abstract

In this paper, we introduce the software suite, Hermes, which provides fast, novel algorithms for RNA secondary structure kinetics. Using the fast Fourier transform to e?ciently compute the Boltzmann probability that a secondary structure S of a given RNA sequence has base pair distance x [resp. y] from reference structure A [resp. B], Hermes computes the exact kinetics of folding from A to B in this coarse-grained model. In particular, Hermes computes the mean ?rst passage time from the transition probability matrix by using matrix inversion, and also computes the equilibrium time from the rate matrix by using spectral decomposition. Due to the model granularity and the speed of Hermes, it is capable of determining secondary structure refolding kinetics for large RNA sequences, beyond the range of other methods. Comparative benchmarking of Hermes with other methods indicates that Hermes provides refolding kinetics of accuracy suitable for use in computational design of RNA, an important area of synthetic biology. Source code and documentation for Hermes are available at http://bioinformatics. bc.edu/clotelab/Hermes/.

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Most cited references 21

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Principles that govern the folding of protein chains.

C ANFINSEN (1973)

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De novo design of a synthetic riboswitch that regulates transcription termination

Manja Wachsmuth, Sven Findeiß, Nadine Weissheimer … (2012)

Riboswitches are regulatory RNA elements typically located in the 5′-untranslated region of certain mRNAs and control gene expression at the level of transcription or translation. These elements consist of a sensor and an adjacent actuator domain. The sensor usually is an aptamer that specifically interacts with a ligand. The actuator contains an intrinsic terminator or a ribosomal binding site for transcriptional or translational regulation, respectively. Ligand binding leads to structural rearrangements of the riboswitch and to presentation or masking of these regulatory elements. Based on this modular organization, riboswitches are an ideal target for constructing synthetic regulatory systems for gene expression. Although riboswitches for translational control have been designed successfully, attempts to construct synthetic elements regulating transcription have failed so far. Here, we present an in silico pipeline for the rational design of synthetic riboswitches that regulate gene expression at the transcriptional level. Using the well-characterized theophylline aptamer as sensor, we designed the actuator part as RNA sequences that can fold into functional intrinsic terminator structures. In the biochemical characterization, several of the designed constructs show ligand-dependent control of gene expression in Escherichia coli, demonstrating that it is possible to engineer riboswitches not only for translational but also for transcriptional regulation.

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On the importance of cotranscriptional RNA structure formation

Daniel LL Lai, Jeff Proctor, Irmtraud M Meyer (2013)

Almost all state-of-the-art methods for prediction accuracy of RNA secondary structure ignore the process of structure formation and focus on the final RNA structure. In this review, the existing evidence for cotranscriptional folding and the currently used strategies for RNA secondary-structure prediction are analyzed. Potential improvements to existing methods that would capture the process of cotranscriptional structure formation are suggested.