Thermodynamic characterization of naturally occurring RNA tetraloops

Sheehy, Justin; Davis, Amber R.; Znosko, Brent M.

doi:10.1261/rna.1773110

Cited by 62 publications

(125 citation statements)

References 62 publications

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“…The nearest neighbor prediction typically deviates from experimental data by 2-3 kJ/mol on GNRA and UNGC tetraloops. 42 As also described above, the Amberχ OL3 force field does not reproduce correctly the folding free energy predicted by the nearest neighbor models. The disagreement is less pronounced for GAGA, while it is dramatic for UUCG tetraloop.…”

mentioning

confidence: 84%

Free Energy Landscape of GAGA and UUCG RNA Tetraloops

Bottaro

Banáš

Šponer

et al. 2016

J. Phys. Chem. Lett.

179

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We report the folding thermodynamics of ccUUCGgg and ccGAGAgg RNA tetraloops using atomistic molecular dynamics simulations. We obtain a previously unreported estimation of the folding free energy using parallel tempering in combination with well-tempered metadynamics. A key ingredient is the use of a recently developed metric distance, eRMSD, as a biased collective variable. We find that the native fold of both tetraloops is not the global free energy minimum using the Amber\c{hi}OL3 force field. The estimated folding free energies are 30.2kJ/mol for UUCG and 7.5 kJ/mol for GAGA, in striking disagreement with experimental data. We evaluate the viability of all possible one-dimensional backbone force field corrections. We find that disfavoring the gauche+ region of {\alpha} and {\zeta} angles consistently improves the existing force field. The level of accuracy achieved with these corrections, however, cannot be considered sufficient by judging on the basis of available thermodynamic data and solution experiments.Comment: Journal of Physical Chemistry Letters (2016

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mentioning

confidence: 84%

Free Energy Landscape of GAGA and UUCG RNA Tetraloops

Bottaro

Banáš

Šponer

et al. 2016

J. Phys. Chem. Lett.

179

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“…The free- energy increment of the loops varied between 3.7 and 4.6 kcal/mol. A simple nearest neighbor model to predict the stability of the RNA hairpin tetraloop has recently been described (Sheehy et al 2010). The model predicts that the GAAA tetraloop would have a free-energy increment of 3.7 kcal/mol, which is slightly less than the average hairpin loop value measured here, 4.1 kcal/mol.…”

Section: Influence Of the Gaaa Tetraloop On Hairpin Stabilitymentioning

confidence: 72%

“…An iterative approach may be necessary, whereby an average value for bulge loop insertion is used initially to develop a set of RNA structures whose free energy is then refined using the model determined above. This may also be necessary for some hairpin structures that have been shown also to exhibit non-nearestneighbor influences (Sheehy et al 2010).…”

Section: Discussionmentioning

confidence: 99%

“…The hairpin loops closed by UA, on average, had a higher free-energy increment than the hairpin loops closed by GC, 4.3 versus 3.8 kcal/mol, respectively. This difference may represent a non-nearest-neighbor interaction (Sheehy et al 2010) or may be related to the stacking of the first mismatch on the closing base pair, as exemplified by the stacking of a mismatch on a terminal base pair of a duplex (Vecenie et al 2006 terminal mismatch is 0.4 kcal/mol, almost exactly the difference observed in the free-energy increment for the two hairpin loops (Hickey and Turner 1985;Sugimoto et al 1987;Sheehy et al 2010). Further investigation will be necessary to determine the origins of the stability differences of the hairpin loops.…”

Section: Influence Of the Gaaa Tetraloop On Hairpin Stabilitymentioning

confidence: 99%

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Stability of single-nucleotide bulge loops embedded in a GAAA RNA hairpin stem

Lim¹,

Merz²,

McCann³

et al. 2012

RNA

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Forty-six RNA hairpins containing combinations of 39 or 59 bulge loops and a 39 or 59 fluorescein label were optically melted in 1 M NaCl, and the thermodynamic parameters DH°, DS°, DG°3 7 , and T M for each hairpin were determined. The bulge loops were of the group I variety, in which the identity of the bulge is known, and the group II variety, in which the bulged nucleotide is identical to one of its nearest neighbors, leading to ambiguity as to the exact position of the bulge. The fluorescein label at either the 39 end or 59 end of the hairpin did not significantly influence the stability of the hairpin. As observed with bulge loops inserted into a duplex motif, the insertion of a bulge loop into the stem of a hairpin loop was destabilizing. The model developed to predict the influence of bulge loops on the stability of duplex formation was extended to predict the influence of bulge loops on hairpin stability. Specifically, the influence of the bulge is related to the stability of the hairpin stem distal from the hairpin loop.

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“…The approach used to determine the statistical potentials for hairpin loops is illustrated with a comparison with recent experimentally derived tetraloop free-energy values 49 . For the 1536 possible combinations (256 hairpin loops × 6 base pairs), 1225 (80%) had an absolute difference less than 0.5 kcal/mol and 1243 (81%) had an absolute difference less than 1.0 kcal/mol.…”

Section: Resultsmentioning

confidence: 99%

Statistical Potentials for Hairpin and Internal Loops Improve the Accuracy of the Predicted RNA Structure

Gardner

Ren

Ozer

et al. 2011

Journal of Molecular Biology

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RNA is directly associated with a growing number of functions within the cell. The accurate prediction of different RNAs higher-order structure from their nucleic acid sequences will provide insight into their functions and molecular mechanics. We have been determining statistical potentials for a collection of structural elements that is larger than the number of structural elements determined with experimentally determined energy values. The experimentally derived free-energies and the statistical potentials for canonical base pair stacks are analogous, demonstrating that statistical potentials derived from comparative data can be used as an alternative energetic parameter. A new computational infrastructure - RNA Comparative Analysis Database (rCAD) - that utilizes a relational database was developed to manipulate and analyze very large sequence alignments and secondary structure datasets. Using rCAD, a richer set of energetic parameters for RNA fundamental structural elements including hairpin and internal loops was determined. A new version of RNAfold was developed to utilize these statistical potentials. Overall, these new statistical potentials for hairpin and internal loops integrated into the new version of RNAfold demonstrated significant improvements in the prediction accuracy of RNA secondary structure.

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Thermodynamic characterization of naturally occurring RNA tetraloops

Cited by 62 publications

References 62 publications

Free Energy Landscape of GAGA and UUCG RNA Tetraloops

Free Energy Landscape of GAGA and UUCG RNA Tetraloops

Stability of single-nucleotide bulge loops embedded in a GAAA RNA hairpin stem

Statistical Potentials for Hairpin and Internal Loops Improve the Accuracy of the Predicted RNA Structure

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