Dynamics‐Based Amplification of RNA Function and Its Characterization by Using NMR Spectroscopy

Al‐Hashimi, Hashim M.

doi:10.1002/cbic.200500002

Cited by 59 publications

(81 citation statements)

References 181 publications

(252 reference statements)

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“…These above results are consistent with the experimental view that the bound TAR RNA is stabilized by weak intermolecular interactions with the ligand 27 and that bound conformations are transiently sampled in the free ensemble, 4,5 following the conformation selection model. The results are also encouraging from an application point of view in that those simulated TAR RNA conformations can be used as receptor structures for docking.…”

Section: Discussionsupporting

confidence: 89%

HIV-1 TAR RNA Spontaneously Undergoes Relevant Apo-to-Holo Conformational Transitions in Molecular Dynamics and Constrained Geometrical Simulations

Fulle

Christ

Kestner

et al. 2010

J. Chem. Inf. Model.

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We report all-atom molecular dynamics and replica exchange molecular dynamics simulations on the unbound human immunodeficiency virus type-1 (HIV-1) transactivation responsive region (TAR) RNA structure and three TAR RNA structures in bound conformations of, in total, ∼250 ns length. We compare the extent of observed conformational sampling with that of the conceptually simpler and computationally much cheaper constrained geometrical simulation approach framework rigidity optimized dynamic algorithm (FRODA). Atomic fluctuations obtained by replica-exchange molecular dynamics (REMD) simulations agree quantitatively with those obtained by molecular dynamics (MD) and FRODA simulations for the unbound TAR structure. Regarding the stereochemical quality of the generated conformations, backbone torsion angles and puckering modes of the sugar-phosphate backbone were reproduced equally well by MD and REMD simulations, but further improvement is needed in the case of FRODA simulations. Essential dynamics analysis reveals that all three simulation approaches show a tendency to sample bound conformations when starting from the unbound TAR structure, with MD and REMD simulations being superior with respect to FRODA. These results are consistent with the experimental view that bound TAR RNA conformations are transiently sampled in the free ensemble, following a conformation selection model. The simulation-generated TAR RNA conformations have been successfully used as receptor structures for docking. This finding has important implications for RNA-ligand docking in that docking into an ensemble of simulation-generated RNA structures is shown to be a valuable means to cope with large apo-to-holo conformational transitions of the receptor structure.

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Section: Discussionsupporting

confidence: 89%

HIV-1 TAR RNA Spontaneously Undergoes Relevant Apo-to-Holo Conformational Transitions in Molecular Dynamics and Constrained Geometrical Simulations

Fulle

Christ

Kestner

et al. 2010

J. Chem. Inf. Model.

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“…Over the past two decades, there has been great interest in understanding the mechanism by which RNA structures undergo adaptive recognition (Hermann and Patel 2000;Williamson 2000; Leulliot and Varani 2001;Al-Hashimi 2005). On the one hand, these studies are motivated by a desire to understand how RNA structures change in response to specific cellular signals while avoiding promiscuous transitions from taking place.…”

Section: Introductionmentioning

confidence: 99%

“…Whether by induced fit, conformational selection, or both, a complete understanding of how RNA structures change adaptively requires the characterization of RNA's intrinsic structural flexibility at the atomic level (Leulliot and Varani 2001;Al-Hashimi 2005;Al-Hashimi and Walter 2008;Hall 2008). Regulatory RNAs must encode-at some level-flexibility that allows their structures to change specifically along functionally productive pathways.…”

Section: Introductionmentioning

confidence: 99%

Domain-elongation NMR spectroscopy yields new insights into RNA dynamics and adaptive recognition

Zhang

Al‐Hashimi

2009

RNA

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By simplifying the interpretation of nuclear magnetic resonance spin relaxation and residual dipolar couplings data, recent developments involving the elongation of RNA helices are providing new atomic insights into the dynamical properties that allow RNA structures to change functionally and adaptively. Domain elongation, in concert with spin relaxation measurements, has allowed the detailed characterization of a hierarchical network of local and collective motional modes occurring at nanosecond timescale that mirror the structural rearrangements that take place following adaptive recognition. The combination of domain elongation with residual dipolar coupling measurements has allowed the experimental threedimensional visualization of very large amplitude rigid-body helix motions in HIV-1 transactivation response element (TAR) that trace out a highly choreographed trajectory in which the helices twist and bend in a correlated manner. The dynamic trajectory allows unbound TAR to sample many of its ligand bound conformations, indicating that adaptive recognition occurs by ''conformational selection'' rather than ''induced fit.'' These studies suggest that intrinsic flexibility plays essential roles directing RNA conformational changes along specific pathways.

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“…4,5 Because of the paucity of 15 N nuclei in RNA and DNA, the richest information resides in studies of 13 C relaxation ( Figure 2). The emphasis of this report is on motions that occur on the ps-ns timescale, with a brief description of techniques used to provide information on slower motions.…”

Section: Introductionmentioning

confidence: 99%

“…Despite their obvious importance, this review does not cover the application of residual dipolar couplings to studies of RNA dynamics, for the sake of retaining focus; the reader is referred to several other excellent papers on this subject. [5][6][7][8] The next section provides Historical Context; section NMR Studies of Nucleic Acids Dynamics introduces common relaxation techniques, and details how they can be applied to nucleic acids. Section Quantitative Analysis of Relaxation Data on RNA and DNA is dedicated to common methods to provide a quantitative analysis, and section Studies of Nucleic Acid Dynamics by 13 C NMR describes some topical application of these methods.…”

Section: Introductionmentioning

confidence: 99%

NMR studies of dynamics in RNA and DNA by ¹³C relaxation

Shajani

Varani

2006

Biopolymers

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T he many functions of RNA in biology very often require this molecule to change its conformation in response to biological signals in the form of small molecules, proteins, or other nucleic acids. 1,2 Although structurally more conservative and therefore dynamically less diverse, local motions in DNA may facilitate protein recognition and allow enzymes acting on DNA to access functional groups on the bases that would otherwise be buried in Watson-Crick base pairs. 3 These statements make a compelling case to study the sequence dependent dynamics in nucleic acids; yet, residue-specific studies of nucleic acid dynamics are relatively few. Fortunately, NMR studies of dynamics of nucleic acids and nucleic acids-protein complexes are gaining increased attention, this spectroscopy being the only way to access information on a residue-by-residue basis. The questions that are being asked are how motion contributes to the affinity and specificity of biological interactions and what trajectories lead to the remarkably large conformational changes that are sometimes observed.RNA and DNA molecules experience motions on a wide range of time scales, ranging from rapid localized motions to much slower collective motions of entire helical domains. Figure 1 summarizes the NMR spectroscopic techniques commonly used to obtain information in each motional regime. Dynamics occurring on time scales that are considered ''fast'' in NMR spectroscopic studies (ps-ns) largely reflects bond librations associated with small amplitude and localized motions.

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Dynamics‐Based Amplification of RNA Function and Its Characterization by Using NMR Spectroscopy

Cited by 59 publications

References 181 publications

HIV-1 TAR RNA Spontaneously Undergoes Relevant Apo-to-Holo Conformational Transitions in Molecular Dynamics and Constrained Geometrical Simulations

HIV-1 TAR RNA Spontaneously Undergoes Relevant Apo-to-Holo Conformational Transitions in Molecular Dynamics and Constrained Geometrical Simulations

Domain-elongation NMR spectroscopy yields new insights into RNA dynamics and adaptive recognition

NMR studies of dynamics in RNA and DNA by ¹³C relaxation

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Dynamics‐Based Amplification of RNA Function and Its Characterization by Using NMR Spectroscopy

Cited by 59 publications

References 181 publications

HIV-1 TAR RNA Spontaneously Undergoes Relevant Apo-to-Holo Conformational Transitions in Molecular Dynamics and Constrained Geometrical Simulations

HIV-1 TAR RNA Spontaneously Undergoes Relevant Apo-to-Holo Conformational Transitions in Molecular Dynamics and Constrained Geometrical Simulations

Domain-elongation NMR spectroscopy yields new insights into RNA dynamics and adaptive recognition

NMR studies of dynamics in RNA and DNA by 13C relaxation

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NMR studies of dynamics in RNA and DNA by ¹³C relaxation