Molecular Dynamics Study of the Controlled Destabilization of an RNA Hairpin Structure by a Covalently Attached Azobenzene Switch

Rastädter, Dominique; Biswas, Mithun; Burghardt, Irène

doi:10.1021/jp501399k

Cited by 22 publications

(55 citation statements)

References 59 publications

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“…The overall stability of the duplex is an interplay between hydrogen‐bonding and base‐stacking interactions. As observed in previous studies,42 a flipped out cis azobenzene disrupts the hydrogen‐bonding interactions between neighboring base pairs, but native‐like base stacking between azobenzene‐neighboring bases is observed. On the other hand, a trans azobenzene stabilizes the duplex due to increased stacking.…”

Section: Resultssupporting

confidence: 77%

Reversible Photoswitching of RNA Hybridization at Room Temperature with an Azobenzene C‐Nucleoside

Goldau

Murayama

Brieke

et al. 2014

Chemistry A European J

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Photoregulation of RNA remains a challenging task as the introduction of a photoswitch entails changes in the shape and the stability of the duplex that strongly depend on the chosen linker strategy. Herein, the influence of a novel nucleosidic linker moiety on the photoregulation efficiency of azobenzene is investigated. To this purpose, two azobenzene C-nucleosides were stereoselectively synthesized, characterized, and incorporated into RNA oligonucleotides. Spectroscopic characterization revealed a reversible and fast switching process, even at 20 °C, and a high thermal stability of the respective cis isomers. The photoregulation efficiency of RNA duplexes upon trans-to-cis isomerization was investigated by using melting point studies and compared with the known D-threoninol-based azobenzene system, revealing a photoswitching amplitude of the new residues exceeding 90 % even at room temperature. Structural changes in the duplexes upon photoisomerization were investigated by using MM/MD calculations. The excellent photoswitching performance at room temperature and the high thermal stability make these new azobenzene residues promising candidates for in-vivo and nanoarchitecture photoregulation applications of RNA.

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Section: Resultssupporting

confidence: 77%

Reversible Photoswitching of RNA Hybridization at Room Temperature with an Azobenzene C‐Nucleoside

Goldau

Murayama

Brieke

et al. 2014

Chemistry A European J

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“…41 The stacking interactions between any two bases can be mapped by monitoring either the center of mass distances or the buried surface area (BSA) between the bases and comparing them against mean values of these parameters obtained from reference simulations. 24,29 Here, we refer to the BSA, as in ref 29, but adopt a slightly modified approach to calculate the stacking stability. Let us consider the distribution of BSA between two bases calculated from a native RNA simulation where the bases remain visually stacked.…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

“…22,28 Our recent modeling works in this field focused on the following two aspects: First, to develop a theoretical framework to capture the effect of the fast photoswitching dynamics on the slow conformational changes in DNA 29 and second, to analyze the destabilization of an RNA hairpin structure by covalently linked trans vs cis-azobenzenes. 24 In the second study, a detailed analysis of the effects of stacking and hydrogen bonding was given for the RNA hairpin structure. Here, melting temperatures were obtained for the azobenzene-substituted hairpin and it was found that T m cis <T m trans <T m native , in good qualitative agreement with experiment.…”

Section: Introductionmentioning

confidence: 99%

In Search of an Efficient Photoswitch for Functional RNA: Design Principles from a Microscopic Analysis of Azobenzene-linker-RNA Dynamics with Different Linkers

et al. 2015

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The design of optimal photoswitches to regulate nucleic acid functionality is a considerable challenge. Azobenzene switches that are covalently bound to the nucleic acid backbone are a paradigm example that has been studied using different types of linker species connecting the chromophore to the backbone. To support experimental efforts to construct optimal azobenzene-linker-RNA combinations, we introduce here a systematic approach for theoretical analysis, which provides criteria for the local embedding of the chromophore via a chosen linker. Using a local reference frame adapted to the chromophore, quantitative measures are provided for (i) the propensity of stacking in competition with a drift toward the minor or major groove, (ii) the tendency to disrupt the native hydrogen bond network, (iii) the structural flexibility of the chromophore-linker combination, and (iv) the correlations with the presence of a base in the opposite strand. Large differences in structural stability between the trans and cis forms of the azobenzene chromophore, according to these criteria, indicate good functionality and lead to significant differences in melting temperatures. In particular, a recently synthesized deoxyribose linker proves optimal within the set of azobenzene-linker-RNA combinations considered.

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“…7−11 Molecular dynamics (MD) simulations can be used to predict structure, 12,13 mechanism, 14 and dynamics 15−18 which can then provide insight into function. RNA MD has been done both atomistically 19−21 and with coarse-graining 22 and has a wide spectrum of applications.…”

Section: Introductionmentioning

confidence: 99%

Stacking in RNA: NMR of Four Tetramers Benchmark Molecular Dynamics

Condon

Kennedy

Mort

et al. 2015

J. Chem. Theory Comput.

105

379

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Molecular dynamics (MD) simulations for RNA tetramers r(AAAA), r(CAAU), r(GACC), and r(UUUU) are benchmarked against 1H–1H NOESY distances and 3J scalar couplings to test effects of RNA torsion parametrizations. Four different starting structures were used for r(AAAA), r(CAAU), and r(GACC), while five starting structures were used for r(UUUU). On the basis of X-ray structures, criteria are reported for quantifying stacking. The force fields, AMBER ff99, parmbsc0, parm99χ_Yil, ff10, and parmTor, all predict experimentally unobserved stacks and intercalations, e.g., base 1 stacked between bases 3 and 4, and incorrect χ, ϵ, and sugar pucker populations. The intercalated structures are particularly stable, often lasting several microseconds. Parmbsc0, parm99χ_Yil, and ff10 give similar agreement with NMR, but the best agreement is only 46%. Experimentally unobserved intercalations typically are associated with reduced solvent accessible surface area along with amino and hydroxyl hydrogen bonds to phosphate nonbridging oxygens. Results from an extensive set of MD simulations suggest that recent force field parametrizations improve predictions, but further improvements are necessary to provide reasonable agreement with NMR. In particular, intramolecular stacking and hydrogen bonding interactions may not be well balanced with the TIP3P water model. NMR data and the scoring method presented here provide rigorous benchmarks for future changes in force fields and MD methods.

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Molecular Dynamics Study of the Controlled Destabilization of an RNA Hairpin Structure by a Covalently Attached Azobenzene Switch

Cited by 22 publications

References 59 publications

Reversible Photoswitching of RNA Hybridization at Room Temperature with an Azobenzene C‐Nucleoside

Reversible Photoswitching of RNA Hybridization at Room Temperature with an Azobenzene C‐Nucleoside

In Search of an Efficient Photoswitch for Functional RNA: Design Principles from a Microscopic Analysis of Azobenzene-linker-RNA Dynamics with Different Linkers

Stacking in RNA: NMR of Four Tetramers Benchmark Molecular Dynamics

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