Classification and energetics of the base-phosphate interactions in RNA

Zirbel, Craig L.; Šponer, Judit E.; Stombaugh, Jesse; Leontis, Neocles B.

doi:10.1093/nar/gkp468

Cited by 156 publications

(303 citation statements)

References 56 publications

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“…The majority of structures that adopt the Triplet structure do not unfold, and the few cases of unfolding only occur through the scission of the G 1 -A 6 base pair. The additional interactions that stabilize this configuration include a base-phosphate interaction between G 7 and the G 1 phosphate group, which has been categorized as the most stable base-phosphate interaction through quantum mechanical calculations at the second-order MollerPlesset level (MP2) (47,48). In our simulations, this interaction was shown to break, while the sheared base pairs between the G 1 and G 7 held.…”

Section: Discussionmentioning

confidence: 90%

Free-energy landscape of a hyperstable RNA tetraloop

Miner

Chen

Garcı́a

2016

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

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We report the characterization of the energy landscape and the folding/unfolding thermodynamics of a hyperstable RNA tetraloop obtained through high-performance molecular dynamics simulations at microsecond timescales. Sampling of the configurational landscape is conducted using temperature replica exchange molecular dynamics over three isochores at high, ambient, and negative pressures to determine the thermodynamic stability and the freeenergy landscape of the tetraloop. The simulations reveal reversible folding/unfolding transitions of the tetraloop into the canonical A-RNA conformation and the presence of two alternative configurations, including a left-handed Z-RNA conformation and a compact purine Triplet. Increasing hydrostatic pressure shows a stabilizing effect on the A-RNA conformation and a destabilization of the lefthanded Z-RNA. Our results provide a comprehensive description of the folded free-energy landscape of a hyperstable RNA tetraloop and highlight the significant advances of all-atom molecular dynamics in describing the unbiased folding of a simple RNA secondary structure motif.RNA | free-energy landscape | molecular dynamics | tetraloop | pressure T he stability of a folded RNA molecule depends on a complex set of interactions between the RNA with itself and the surrounding environment. Secondary RNA structures fold by a combination of complimentary base pairing, nucleotide stacking, and screening of the anionic phosphate backbone (1), but these interactions depend heavily on the local solution environment, and the RNA configuration can be either stabilized or destabilized by a number of extrinsic factors, including temperature (2), pressure (3), denaturants, and salt concentration (4). Even in simple RNA duplexes, changes in pressure and ion concentrations have been shown to drive the formation of alternative configurations (5, 6) and change the RNA folded ensemble. Characterizing the effects that these different factors have on the folded free-energy landscape of RNA is crucial for determining the thermodynamic stability of different RNA motifs and the probability of transitions between configurations.Small RNA hairpins have been used as a model system for characterizing RNA folding and stability for decades because of their small size, their ubiquitous presence in many natural systems, and the complexity of their internal interactions (7-11). Hairpins result when a single oligonucleotide strand bends 180°t o form an antiparallel duplex through complementary base pairing. The bent, single-stranded loop region is capable of forming complex hydrogen bond networks (12) or long-range interactions with other RNAs (13). Some of the most thermodynamically stable RNA hairpins form loop regions of 4 nt, called tetraloops (14), which are highly compact, structurally conserved, and typically stabilized by the formation of a network of hydrogen bonds (15) that decrease the loop conformational entropy.These tetraloop structures have been explored through multiple experimental (16-23) and computational...

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Section: Discussionmentioning

confidence: 90%

Free-energy landscape of a hyperstable RNA tetraloop

Miner

Chen

Garcı́a

2016

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

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“…Apo simulation 1, however, has G76 and U34 stacked at the end of P3. The noncanonical pairs are annotated according to the standard Leontis-Westhof classification (Leontis et al 2002;Zirbel et al 2009). The SD sequence is highlighted in yellow.…”

Section: Supports the Formation Of An Additional Expected Pair Inmentioning

confidence: 99%

Molecular mechanism for preQ₁-II riboswitch function revealed by molecular dynamics

Aytenfisu

Liberman

Wedekind

et al. 2015

RNA

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Riboswitches are RNA molecules that regulate gene expression using conformational change, affected by binding of small molecule ligands. A crystal structure of a ligand-bound class II preQ 1 riboswitch has been determined in a previous structural study. To gain insight into the dynamics of this riboswitch in solution, eight total molecular dynamic simulations, four with and four without ligand, were performed using the Amber force field. In the presence of ligand, all four of the simulations demonstrated rearranged base pairs at the 3 ′ end, consistent with expected base-pairing from comparative sequence analysis in a prior bioinformatic analysis; this suggests the pairing in this region was altered by crystallization. Additionally, in the absence of ligand, three of the simulations demonstrated similar changes in base-pairing at the ligand binding site. Significantly, although most of the riboswitch architecture remained intact in the respective trajectories, the P3 stem was destabilized in the ligand-free simulations in a way that exposed the Shine-Dalgarno sequence. This work illustrates how destabilization of two major groove base triples can influence a nearby H-type pseudoknot and provides a mechanism for control of gene expression by a fold that is frequently found in bacterial riboswitches.

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“…Modeling such extended conformations may require long-range interactions, but such distances are lacking in X-ray structures of globular native RNA. To better address this problem, and possibly improve the geometry of base-interactions, we envision having to explicitly include base-pairing interactions or other orientation-dependent interactions like those used in recent studies (Dima et al 2005;Stombaugh et al 2009;Zirbel et al 2009). In future work, we will look at structural refinement of Comparison of the best scoring decoys for the GUAA tetraloop (PDB id: 1msy).…”

Section: Fully Differentiable Potentials For Refinement and Modelingmentioning

confidence: 99%

Fully differentiable coarse-grained and all-atom knowledge-based potentials for RNA structure evaluation

Bernauer¹,

Huang

Sim³

et al. 2011

RNA

128

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RNA molecules play integral roles in gene regulation, and understanding their structures gives us important insights into their biological functions. Despite recent developments in template-based and parameterized energy functions, the structure of RNA-in particular the nonhelical regions-is still difficult to predict. Knowledge-based potentials have proven efficient in protein structure prediction. In this work, we describe two differentiable knowledge-based potentials derived from a curated data set of RNA structures, with all-atom or coarse-grained representation, respectively. We focus on one aspect of the prediction problem: the identification of native-like RNA conformations from a set of near-native models. Using a variety of near-native RNA models generated from three independent methods, we show that our potential is able to distinguish the native structure and identify native-like conformations, even at the coarse-grained level. The all-atom version of our knowledge-based potential performs better and appears to be more effective at discriminating near-native RNA conformations than one of the most highly regarded parameterized potential. The fully differentiable form of our potentials will additionally likely be useful for structure refinement and/or molecular dynamics simulations.

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Classification and energetics of the base-phosphate interactions in RNA

Cited by 156 publications

References 56 publications

Free-energy landscape of a hyperstable RNA tetraloop

Free-energy landscape of a hyperstable RNA tetraloop

Molecular mechanism for preQ₁-II riboswitch function revealed by molecular dynamics

Fully differentiable coarse-grained and all-atom knowledge-based potentials for RNA structure evaluation

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Classification and energetics of the base-phosphate interactions in RNA

Cited by 156 publications

References 56 publications

Free-energy landscape of a hyperstable RNA tetraloop

Free-energy landscape of a hyperstable RNA tetraloop

Molecular mechanism for preQ1-II riboswitch function revealed by molecular dynamics

Fully differentiable coarse-grained and all-atom knowledge-based potentials for RNA structure evaluation

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Molecular mechanism for preQ₁-II riboswitch function revealed by molecular dynamics