Quantifying the energetic interplay of RNA tertiary and secondary structure interactions

Silverman, Scott; Zheng, Minxue; Wu, Ming; Tinoco, Ignacio; Cech, Thomas R.

doi:10.1017/s1355838299991823

Cited by 59 publications

(71 citation statements)

References 20 publications

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“…NMR and nondenaturing gel data of two tP5abc mutants A186U (Fig. 2 b and c) and U167C (17) have shown that both mutants adopt the extended form and do not fold in Mg 2ϩ . Finally, the slow exchange rate between the folded and extended P5abc measured by NMR also suggests that an extended P5abc can exist as a stable structural intermediate.…”

Section: Discussionmentioning

confidence: 98%

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Formation of a GNRA tetraloop in P5abc can disrupt an interdomain interaction in the Tetrahymena group I ribozyme

Zheng

Tinoco

2001

Proc. Natl. Acad. Sci. U.S.A.

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The secondary structure of a truncated P5abc subdomain (tP5abc, a 56-nucleotide RNA) of the Tetrahymena thermophila group I intron ribozyme changes when its tertiary structure forms. We have now used heteronuclear NMR spectroscopy to determine its conformation in solution. The tP5abc RNA that contains only secondary structure is extended compared with the tertiary folded form; both forms coexist in slow chemical exchange (the interconversion rate constant is slower than 1 s ؊1 ) in the presence of magnesium. Kinetic experiments have shown that tertiary folding of the P5abc subdomain is one of the earliest folding transitions in the group I intron ribozyme, and that it leads to a metastable misfolded intermediate. Previous mutagenesis studies suggest that formation of the extended P5abc structure described here destabilize a misfolded intermediate. This study shows that the P5abc RNA subdomain containing a GNRA tetraloop in P5c (in contrast to the five-nucleotide loop P5c in the tertiary folded ribozyme) can disrupt the base-paired interdomain (P14) interaction between P5c and P2.

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Section: Discussionmentioning

confidence: 98%

“…The NMR-determined secondary structure of tP5abc is consistent with the lowest free energy form predicted by using the Zuker folding algorithm (3); we call this structure the extended form. Tertiary interactions upon folding of the extended form offset the free energy increase caused by the change in secondary structure (17).…”

mentioning

confidence: 99%

Formation of a GNRA tetraloop in P5abc can disrupt an interdomain interaction in the Tetrahymena group I ribozyme

Zheng

Tinoco

2001

Proc. Natl. Acad. Sci. U.S.A.

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“…Two alternative scenarios for the time-course of RNA folding are possible: (1) the sequential hierarchical folding, where the secondary structure forms first, then tertiary contacts finally shape a specific tertiary structure (Tinoco and Bustamante 1999); and (2) the mutually dependent interplay of RNA secondary and tertiary interactions, where substantial rearrangement of folding intermediates successively takes place (Silverman et al 1999). We posit that using simplified models for folding RNA is apt for investigating RNA folding mechanisms in de novo RNA fragments, as no assumptions regarding the folding mechanisms are made a priori.…”

Section: Discussionmentioning

confidence: 99%

Ab initio RNA folding by discrete molecular dynamics: From structure prediction to folding mechanisms

Ding

Sharma

Chalasani

et al. 2008

RNA

268

385

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RNA molecules with novel functions have revived interest in the accurate prediction of RNA three-dimensional (3D) structure and folding dynamics. However, existing methods are inefficient in automated 3D structure prediction. Here, we report a robust computational approach for rapid folding of RNA molecules. We develop a simplified RNA model for discrete molecular dynamics (DMD) simulations, incorporating base-pairing and base-stacking interactions. We demonstrate correct folding of 150 structurally diverse RNA sequences. The majority of DMD-predicted 3D structures have <4 Å deviations from experimental structures. The secondary structures corresponding to the predicted 3D structures consist of 94% native base-pair interactions. Folding thermodynamics and kinetics of tRNA Phe , pseudoknots, and mRNA fragments in DMD simulations are in agreement with previous experimental findings. Folding of RNA molecules features transient, non-native conformations, suggesting nonhierarchical RNA folding. Our method allows rapid conformational sampling of RNA folding, with computational time increasing linearly with RNA length. We envision this approach as a promising tool for RNA structural and functional analyses.

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“…It was reported that Φ-values were considered reliable only for protein mutations whose effect on the stability of the native state exceeded 1.6 kcal/mol [55]. From the experimental data we have for P4-P6 that ∆C209 deletion stabilizes folding of P4-P6 [56] by 1.1 kcal/mol, and the estimated ∆∆G is 0.4 kcal/mol for the destabilizing U168C:U177G double mutation [57]. The dual observations of a large ∆G # value and an early transition state (low Φ) suggest that a simple two-state energy diagram for the P4-P6 tertiary folding is incomplete [16].…”

Section: Prediction Of Folding Nuclei For Domain P4-p6 From the Tetramentioning

confidence: 99%

Theoretical Search for RNA Folding Nuclei

Pereyaslavets

Galzitskaya

2015

Entropy

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Abstract:The functions of RNA molecules are defined by their spatial structure, whose folding is regulated by numerous factors making RNA very similar to proteins. Prediction of RNA folding nuclei gives the possibility to take a fresh look at the problems of the multiple folding pathways of RNA molecules and RNA stability. The algorithm previously developed for prediction of protein folding nuclei has been successfully applied to ~150 various RNA structures: hairpins, tRNAs, structures with pseudoknots, and the large structured P4-P6 domain of the Tetrahymena group I intron RNA. The calculated Φ-values for tRNA structures agree with the experimental data obtained earlier. According to the experiment the nucleotides of the D and T hairpin loops are the last to be involved in the tRNA tertiary structure. Such agreement allowed us to do a prediction for an example of large structured RNA, the P4-P6 RNA domain. One of the advantages of our method is that it allows us to make predictions about the folding nucleus for nontrivial RNA motifs: pseudoknots and tRNA.

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Quantifying the energetic interplay of RNA tertiary and secondary structure interactions

Cited by 59 publications

References 20 publications

Formation of a GNRA tetraloop in P5abc can disrupt an interdomain interaction in the Tetrahymena group I ribozyme

Formation of a GNRA tetraloop in P5abc can disrupt an interdomain interaction in the Tetrahymena group I ribozyme

Ab initio RNA folding by discrete molecular dynamics: From structure prediction to folding mechanisms

Theoretical Search for RNA Folding Nuclei

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