Dataset Information

Tertiary structure-based analysis of microRNA-target interactions.

ABSTRACT: Current computational analysis of microRNA interactions is based largely on primary and secondary structure analysis. Computationally efficient tertiary structure-based methods are needed to enable more realistic modeling of the molecular interactions underlying miRNA-mediated translational repression. We incorporate algorithms for predicting duplex RNA structures, ionic strength effects, duplex entropy and free energy, and docking of duplex-Argonaute protein complexes into a pipeline to model and predict miRNA-target duplex binding energies. To ensure modeling accuracy and computational efficiency, we use an all-atom description of RNA and a continuum description of ionic interactions using the Poisson-Boltzmann equation. Our method predicts the conformations of two constructs of Caenorhabditis elegans let-7 miRNA-target duplexes to an accuracy of ?3.8 Å root mean square distance of their NMR structures. We also show that the computed duplex formation enthalpies, entropies, and free energies for eight miRNA-target duplexes agree with titration calorimetry data. Analysis of duplex-Argonaute docking shows that structural distortions arising from single-base-pair mismatches in the seed region influence the activity of the complex by destabilizing both duplex hybridization and its association with Argonaute. Collectively, these results demonstrate that tertiary structure-based modeling of miRNA interactions can reveal structural mechanisms not accessible with current secondary structure-based methods.

SUBMITTER: Gan HH

PROVIDER: S-EPMC3677264 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Tertiary structure-based analysis of microRNA-target interactions.

Gan Hin Hark HH Gunsalus Kristin C KC

RNA (New York, N.Y.) 20130215 4

Current computational analysis of microRNA interactions is based largely on primary and secondary structure analysis. Computationally efficient tertiary structure-based methods are needed to enable more realistic modeling of the molecular interactions underlying miRNA-mediated translational repression. We incorporate algorithms for predicting duplex RNA structures, ionic strength effects, duplex entropy and free energy, and docking of duplex-Argonaute protein complexes into a pipeline to model a ...[more]

PMID: 23417009

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Project description:BACKGROUND:miRNAs regulate the expression of several genes with one miRNA able to target multiple genes and with one gene able to be simultaneously targeted by more than one miRNA. Therefore, it has become indispensable to shorten the long list of miRNA-target interactions to put in the spotlight in order to gain insight into understanding the regulatory mechanism orchestrated by miRNAs in various cellular processes. A reasonable solution is certainly to prioritize miRNA-target interactions to maximize the effectiveness of the downstream analysis. RESULTS:We propose a new and easy-to-use web tool MIENTURNET (MicroRNA ENrichment TURned NETwork) that receives in input a list of miRNAs or mRNAs and tackles the problem of prioritizing miRNA-target interactions by performing a statistical analysis followed by a fully featured network-based visualization and analysis. The statistics is used to assess the significance of an over-representation of miRNA-target interactions and then MIENTURNET filters based on the statistical significance associated with each miRNA-target interaction. In addition, the holistic approach of the network theory is used to infer possible evidences of miRNA regulation by capturing emergent properties of the miRNA-target regulatory network that would be not evident through a pairwise analysis of the individual components. CONCLUSION:MIENTURNET offers the possibility to consistently perform both statistical and network-based analyses by using only a single tool leading to a more effective prioritization of the miRNA-target interactions. This has the potential to avoid researchers without computational and informatics skills to navigate multiple websites and thus to independently investigate miRNA activity in every cellular process of interest in an easy and at the same time exhaustive way thanks to the intuitive web interface. The web application along with a well-documented and comprehensive user guide are freely available at http://userver.bio.uniroma1.it/apps/mienturnet/ without any login requirement.

Dataset Information

Tertiary structure-based analysis of microRNA-target interactions.

Publications

Tertiary structure-based analysis of microRNA-target interactions.

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