Molecular mechanism of the site-specific self-cleavage of the RNA phosphodiester backbone by a twister ribozyme

Świderek, Katarzyna; Martí, Sérgio; Tuñón, Iñaki; Moliner, Vicent; Bertrán, Juan

doi:10.1007/s00214-017-2060-8

Cited by 6 publications

(14 citation statements)

References 40 publications

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“…The definition of the limits of an "active" inline attack geometry was established by York and co-workers, as the one that has an O2′-P′O5′ angle of more than 125° and O2′-P distance of less than 3.5 Å [57]. This behavior is confirmed in previous studies of related models, where reactive conformations appear less often during MD simulations with the calculated probabilities not higher than 7.7% [57][58][59].…”

Section: Molecular Dynamics Simulationssupporting

confidence: 55%

Theoretical Studies of the Self Cleavage Pistol Ribozyme Mechanism

et al. 2021

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Ribozymes are huge complex biological catalysts composed of a combination of RNA and proteins. Nevertheless, there is a reduced number of small ribozymes, the self-cleavage ribozymes, that are formed just by RNA and, apparently, they existed in cells of primitive biological systems. Unveiling the details of these “fossils” enzymes can contribute not only to the understanding of the origins of life but also to the development of new simplified artificial enzymes. A computational study of the reactivity of the pistol ribozyme carried out by means of classical MD simulations and QM/MM hybrid calculations is herein presented to clarify its catalytic mechanism. Analysis of the geometries along independent MD simulations with different protonation states of the active site basic species reveals that only the canonical system, with no additional protonation changes, renders reactive conformations. A change in the coordination sphere of the Mg2+ ion has been observed during the simulations, which allows proposing a mechanism to explain the unique mode of action of the pistol ribozyme by comparison with other ribozymes. The present results are at the center of the debate originated from recent experimental and theoretical studies on pistol ribozyme.

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Section: Molecular Dynamics Simulationssupporting

confidence: 55%

Theoretical Studies of the Self Cleavage Pistol Ribozyme Mechanism

et al. 2021

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“…Thus, some general acid and general base present at the active site should be involved in the self-cleavage mechanism. 1274 Notably, in some of the available crystal structures, the U-1(2′-OH) nucleophile was not positioned in an in-line attack conformation relative to the scissile phosphate. 1271 , 1272 The absence of this conformation was explained by crystal packing artifacts, leading to extrusion of the U-1 nucleotide from the active site and rearrangements of the sugar–phosphate backbone around the scissile phosphate.…”

Section: Simulations Of Specific Rna Systemsmentioning

confidence: 99%

RNA Structural Dynamics As Captured by Molecular Simulations: A Comprehensive Overview

et al. 2018

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With both catalytic and genetic functions, ribonucleic acid (RNA) is perhaps the most pluripotent chemical species in molecular biology, and its functions are intimately linked to its structure and dynamics. Computer simulations, and in particular atomistic molecular dynamics (MD), allow structural dynamics of biomolecular systems to be investigated with unprecedented temporal and spatial resolution. We here provide a comprehensive overview of the fast-developing field of MD simulations of RNA molecules. We begin with an in-depth, evaluatory coverage of the most fundamental methodological challenges that set the basis for the future development of the field, in particular, the current developments and inherent physical limitations of the atomistic force fields and the recent advances in a broad spectrum of enhanced sampling methods. We also survey the closely related field of coarse-grained modeling of RNA systems. After dealing with the methodological aspects, we provide an exhaustive overview of the available RNA simulation literature, ranging from studies of the smallest RNA oligonucleotides to investigations of the entire ribosome. Our review encompasses tetranucleotides, tetraloops, a number of small RNA motifs, A-helix RNA, kissing-loop complexes, the TAR RNA element, the decoding center and other important regions of the ribosome, as well as assorted others systems. Extended sections are devoted to RNA–ion interactions, ribozymes, riboswitches, and protein/RNA complexes. Our overview is written for as broad of an audience as possible, aiming to provide a much-needed interdisciplinary bridge between computation and experiment, together with a perspective on the future of the field.

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“…The theoretical studies with an implicit model of the solvent, as well as the QM/MM calculations, for similar systems to the one studied in the present paper, lead to equivalent energy profiles in which the TS2 is the transition state of highest energy. ,,− As it has been mentioned in the Computational Methods section, two options can be envisaged in the use of a continuum model for the solvent: to work with the geometries of the stationary points in gas phase or the geometries optimized in solution. In our case, we have not found notable modifications when optimizing in solution (see Tables and S2), and so the first option becomes acceptable.…”

Section: Discussion and Concluding Remarksmentioning

confidence: 89%

“…Four theoretical studies, using quantum mechanics/molecular mechanics (QM/MM) with a nonpolarizable force field, have shown that this is what happens in the case of the Hairpin ribozyme − but not in the Twister ribozyme . In two of these papers, , the proton transfer that activates the nucleophile precedes the nucleophilic attack, while both processes are simultaneous in the other two. , …”

Section: Introductionmentioning

confidence: 99%

Phosphoryl Transfer Reaction in RNA: Is the Substrate-Assisted Catalysis a Possible Mechanism in Certain Solvents?

et al. 2017

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A proton shuttle mechanism for the phosphoryl transfer reaction in RNA, in which a proton is transferred from the nucleophile to the leaving group through a nonbridged oxygen atom of the phosphate, was explored using the MO6-2X density functional method and the solvent continuum model. This reaction is the initial step of the RNA hydrolysis. We used different solvents characterized by their dielectric constant, and, for each of them, we studied the nuclear and electronic relaxation, produced by the solvent reaction field, for the stationary points. Given that RNA has a poor leaving group, the bond breaking corresponds to the rate-determining step. If the O atom is substituted by a S atom, the leaving group is now good, and the rate-determining step is now the nucleophilic attack concerted with the proton transfer. The most relevant result we found is that none of the solvents we studied has a free energy of activation that is smaller than the one in water. This suggests that the enzyme catalysis following this mechanism must be due to the permanent electric field that is created by a preorganized charge distribution but not to the solvent reaction field.

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Molecular mechanism of the site-specific self-cleavage of the RNA phosphodiester backbone by a twister ribozyme

Cited by 6 publications

References 40 publications

Theoretical Studies of the Self Cleavage Pistol Ribozyme Mechanism

Theoretical Studies of the Self Cleavage Pistol Ribozyme Mechanism

RNA Structural Dynamics As Captured by Molecular Simulations: A Comprehensive Overview

Phosphoryl Transfer Reaction in RNA: Is the Substrate-Assisted Catalysis a Possible Mechanism in Certain Solvents?

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