<i>RNA-Puzzles</i>: A CASP-like evaluation of RNA three-dimensional structure prediction

Cruz, José Almeida; Blanchet, Marc Frédérick; Boniecki, Michał; Bujnicki, Janusz M.; Chen, Shi‐Jie; Cao, Song; Das, Rhiju; Ding, Feng; Dokholyan, Nikolay V.; Flores, Samuel Coulbourn; Huang, Lili; Lavender, Christopher A.; Lisi, Véronique; Major, François; Mikolajczak, Katarzyna; Patel, Dinshaw J.; Philips, Anna; Puton, Tomasz; SantaLucia, John; Sijenyi, Fredrick; Hermann, Thomas; Rother, Kristian; Rother, Magdalena B.; Serganov, Alexander; Skorupski, Marcin; Sołtysiński, Tomasz; Sripakdeevong, Parin; Tuszyńska, Irina; Weeks, Kevin M.; Waldsich, Christina; Wildauer, Michael; Leontis, Neocles B.; Westhof, Éric

doi:10.1261/rna.031054.111

Cited by 274 publications

(318 citation statements)

References 71 publications

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“…Thus, X-ray interferometry can be readily predicted from MD simulations and should therefore be valuable in testing and refining MD-based models. A community-wide competition for predicting flexible nucleic acids structures using X-ray interferometry as experimental benchmark would be a powerful addition to the current RNA CASP (46), which currently predicts only folded RNA structures; obtaining the correct weighting of an ensemble of structures is a more stringent test than the correct prediction of a single most-stable structure and is necessary to understand and effectively predict thermodynamics and kinetics.…”

Section: Discussionmentioning

confidence: 99%

From a structural average to the conformational ensemble of a DNA bulge

Shi¹,

Beauchamp

Harbury

et al. 2014

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

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Direct experimental measurements of conformational ensembles are critical for understanding macromolecular function, but traditional biophysical methods do not directly report the solution ensemble of a macromolecule. Small-angle X-ray scattering interferometry has the potential to overcome this limitation by providing the instantaneous distance distribution between pairs of gold-nanocrystal probes conjugated to a macromolecule in solution. Our X-ray interferometry experiments reveal an increasing bend angle of DNA duplexes with bulges of one, three, and five adenosine residues, consistent with previous FRET measurements, and further reveal an increasingly broad conformational ensemble with increasing bulge length. The distance distributions for the AAA bulge duplex (3A-DNA) with six different Au-Au pairs provide strong evidence against a simple elastic model in which fluctuations occur about a single conformational state. Instead, the measured distance distributions suggest a 3A-DNA ensemble with multiple conformational states predominantly across a region of conformational space with bend angles between 24 and 85 degrees and characteristic bend directions and helical twists and displacements. Additional X-ray interferometry experiments revealed perturbations to the ensemble from changes in ionic conditions and the bulge sequence, effects that can be understood in terms of electrostatic and stacking contributions to the ensemble and that demonstrate the sensitivity of X-ray interferometry. Combining X-ray interferometry ensemble data with molecular dynamics simulations gave atomic-level models of representative conformational states and of the molecular interactions that may shape the ensemble, and fluorescence measurements with 2-aminopurinesubstituted 3A-DNA provided initial tests of these atomistic models. More generally, X-ray interferometry will provide powerful benchmarks for testing and developing computational methods. helix-junction-helix | SAXSA grand challenge in biology is to understand the complex free-energy landscape of macromolecules and to decipher the resulting conformational ensembles. To perform their biological functions, macromolecules must adopt a multiplicity of conformations. Balancing and controlling different conformational states is central to biological processes including protein folding, allostery and signaling, and the stepwise assembly and function of macromolecular machines. To understand these complex molecules requires characterization of their free-energy landscapes-i.e., their equilibrium conformational ensembles. Precise measurements of conformational ensembles could allow quantitative modeling of the folding and function of biological macromolecules, would provide valuable experimental data to test current computational models and assumptions, and might facilitate the rational design of specifically acting inhibitors (1, 2).Techniques including NMR and EPR relaxation have been developed to incisively probe motions in the ensemble on different time scales, ranging from pic...

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Section: Discussionmentioning

confidence: 99%

From a structural average to the conformational ensemble of a DNA bulge

Shi¹,

Beauchamp

Harbury

et al. 2014

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

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“…1) in complex with the S6 and S18 proteins was modeled using methodology previously validated in the course of the RNA-puzzles experiment (Cruz et al 2012). A part of an RNA helix and a loop were modeled using the comparative approach with ModeRNA (Rother et al 2011).…”

Section: Sequence Analysismentioning

confidence: 99%

S6:S18 ribosomal protein complex interacts with a structural motif present in its own mRNA

Matelska

Purta

Panek

et al. 2013

RNA

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Prokaryotic ribosomal protein genes are typically grouped within highly conserved operons. In many cases, one or more of the encoded proteins not only bind to a specific site in the ribosomal RNA, but also to a motif localized within their own mRNA, and thereby regulate expression of the operon. In this study, we computationally predicted an RNA motif present in many bacterial phyla within the 5 ′ untranslated region of operons encoding ribosomal proteins S6 and S18. We demonstrated that the S6:S18 complex binds to this motif, which we hereafter refer to as the S6:S18 complex-binding motif (S6S18CBM). This motif is a conserved CCG sequence presented in a bulge flanked by a stem and a hairpin structure. A similar structure containing a CCG trinucleotide forms the S6:S18 complex binding site in 16S ribosomal RNA. We have constructed a 3D structural model of a S6:S18 complex with S6S18CBM, which suggests that the CCG trinucleotide in a specific structural context may be specifically recognized by the S18 protein. This prediction was supported by site-directed mutagenesis of both RNA and protein components. These results provide a molecular basis for understanding protein-RNA recognition and suggest that the S6S18CBM is involved in an auto-regulatory mechanism.

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“…Experimental data, newly collected (Cordero et al 2014), can be also used as constraints during the prediction process. Until now, 16 puzzles have been set up and assessments of six puzzles were previously published (Cruz et al 2012;Miao et al 2015). In the recent and ongoing stages of RNA-Puzzles, we have strongly encouraged the development of novel, automatic, and efficient RNA structure prediction algorithms to help the community in understanding real-world RNA structure-function relationships, as well as to promote the development of automated and user-friendly web servers.…”

Section: Introductionmentioning

confidence: 99%

RNA-Puzzles Round III: 3D RNA structure prediction of five riboswitches and one ribozyme

Miao

Adamiak

Antczak

et al. 2017

RNA

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185

209

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RNA-Puzzles is a collective experiment in blind 3D RNA structure prediction. We report here a third round of RNA-Puzzles. Five puzzles, 4, 8, 12, 13, 14, all structures of riboswitch aptamers and puzzle 7, a ribozyme structure, are included in this round of the experiment. The riboswitch structures include biological binding sites for small molecules (S-adenosyl methionine, cyclic diadenosine monophosphate, 5-amino 4-imidazole carboxamide riboside 5 ′ -triphosphate, glutamine) and proteins (YbxF), and one set describes large conformational changes between ligand-free and ligand-bound states. The Varkud satellite ribozyme is the most recently solved structure of a known large ribozyme. All puzzles have established biological functions and require structural understanding to appreciate their molecular mechanisms. Through the use of fast-track experimental data, including multidimensional chemical mapping, and accurate prediction of RNA secondary structure, a large portion of the contacts in 3D have been predicted correctly leading to similar topologies for the top ranking predictions. Template-based and homologyderived predictions could predict structures to particularly high accuracies. However, achieving biological insights from de novo prediction of RNA 3D structures still depends on the size and complexity of the RNA. Blind computational predictions of RNA structures already appear to provide useful structural information in many cases. Similar to the previous RNA-Puzzles Round II experiment, the prediction of non-Watson-Crick interactions and the observed high atomic clash scores reveal a notable need for an algorithm of improvement. All prediction models and assessment results are available at http://ahsoka.ustrasbg.fr/rnapuzzles/.

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RNA-Puzzles: A CASP-like evaluation of RNA three-dimensional structure prediction

Cited by 274 publications

References 71 publications

From a structural average to the conformational ensemble of a DNA bulge

From a structural average to the conformational ensemble of a DNA bulge

S6:S18 ribosomal protein complex interacts with a structural motif present in its own mRNA

RNA-Puzzles Round III: 3D RNA structure prediction of five riboswitches and one ribozyme

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