Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 38, Pages 15271-15276Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1203831109
Keywords
post-transcriptional regulation; evolutionary computation; computational RNA design; RNA synthetic biology
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Funding
- Actions Thematiques Incitatives de Genopole
- Fondation pour la Recherche Medicale
- European Molecular Biology Organization
- Marie Curie actions [ALTF-1177-2011]
- AXA
- [FP7-ICT-043338]
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A grand challenge in synthetic biology is to use our current knowledge of RNA science to perform the automatic engineering of completely synthetic sequences encoding functional RNAs in living cells. We report here a fully automated design methodology and experimental validation of synthetic RNA interaction circuits working in a cellular environment. The computational algorithm, based on a physicochemical model, produces novel RNA sequences by exploring the space of possible sequences compatible with predefined structures. We tested our methodology in Escherichia coli by designing several positive riboregulators with diverse structures and interaction models, suggesting that only the energy of formation and the activation energy (free energy barrier to overcome for initiating the hybridization reaction) are sufficient criteria to engineer RNA interaction and regulation in bacteria. The designed sequences exhibit nonsignificant similarity to any known noncoding RNA sequence. Our riboregulatory devices work independently and in combination with transcription regulation to create complex logic circuits. Our results demonstrate that a computational methodology based on first-principles can be used to engineer interacting RNAs with allosteric behavior in living cells.
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