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Chin, Kevin; Sharp, Kim A.; Honig, Barry; Pyle, Anna Marie

doi:10.1038/14940

Cited by 195 publications

(38 citation statements)

References 43 publications

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“…The answer is still likely to be yes. First, it has been proposed that the absence of positively charged groups makes the major groove of the G·U pair an attractive target for metal ions, not the absolute value of the electrostatic potential (18). Second, we have shown that the reason that most Motif I G·U pairs have similar major groove electrostatic potential to WC base pairs is the larger cross-strand phosphate distance.…”

Section: Discussionmentioning

confidence: 99%

“…The molecular surfaces of RNA molecules display unique electrostatic patterns that are important for recognition and binding of cationic species [for example, see references (18,35)]. Therefore, careful quantitative characterization of electrostatic features of RNA structural elements, such as the G·U pair, is vital for a better understanding of RNA ligand recognition events.…”

Section: Introductionmentioning

confidence: 99%

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The electrostatic characteristics of G{middle dot}U wobble base pairs

Landon

Greenbaum

et al. 2007

Nucleic Acids Research

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G·U wobble base pairs are the most common and highly conserved non-Watson–Crick base pairs in RNA. Previous surface maps imply uniformly negative electrostatic potential at the major groove of G·U wobble base pairs embedded in RNA helices, suitable for entrapment of cationic ligands. In this work, we have used a Poisson–Boltzmann approach to gain a more detailed and accurate characterization of the electrostatic profile. We found that the major groove edge of an isolated G·U wobble displays distinctly enhanced negativity compared with standard GC or AU base pairs; however, in the context of different helical motifs, the electrostatic pattern varies. G·U wobbles with distinct widening have similar major groove electrostatic potentials to their canonical counterparts, whereas those with minimal widening exhibit significantly enhanced electronegativity, ranging from 0.8 to 2.5 kT/e, depending upon structural features. We propose that the negativity at the major groove of G·U wobble base pairs is determined by the combined effect of the base atoms and the sugar-phosphate backbone, which is impacted by stacking pattern and groove width as a result of base sequence. These findings are significant in that they provide predictive power with respect to which G·U sites in RNA are most likely to bind cationic ligands.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The electrostatic characteristics of G{middle dot}U wobble base pairs

Landon

Greenbaum

et al. 2007

Nucleic Acids Research

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“…The utility of the electrostatic potential for gaining understanding of the function of proteins 1 and nucleic acids 2 has long been established. 1,[3][4][5][6][7][8][9][10][11][12][13][14] Electrostatic effects can be expected to be critical to the function of viruses; 15,16 in the emerging field of nanomaterials, electrostatic properties of viral capsids have been exploited to package nonviral cargoes.…”

Section: Introductionmentioning

confidence: 99%

An analytical approach to computing biomolecular electrostatic potential. II. Validation and applications

Gordon

Fenley

Onufriev

2008

The Journal of Chemical Physics

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An ability to efficiently compute the electrostatic potential produced by molecular charge distributions under realistic solvation conditions is essential for a variety of applications. Here, the simple closed-form analytical approximation to the Poisson equation rigorously derived in Part I for idealized spherical geometry is tested on realistic shapes. The effects of mobile ions are included at the Debye-Hückel level. The accuracy of the resulting closed-form expressions for electrostatic potential is assessed through comparisons with numerical Poisson-Boltzmann ͑NPB͒ reference solutions on a test set of 580 representative biomolecular structures under typical conditions of aqueous solvation. For each structure, the deviation from the reference is computed for a large number of test points placed near the dielectric boundary ͑molecular surface͒. The accuracy of the approximation, averaged over all test points in each structure, is within 0.6 kcal/ mol/ ͉e͉ϳkT per unit charge for all structures in the test set. For 91.5% of the individual test points, the deviation from the NPB potential is within 0.6 kcal/ mol/ ͉e͉. The deviations from the reference decrease with increasing distance from the dielectric boundary: The approximation is asymptotically exact far away from the source charges. Deviation of the overall shape of a structure from ideal spherical does not, by itself, appear to necessitate decreased accuracy of the approximation. The largest deviations from the NPB reference are found inside very deep and narrow indentations that occur on the dielectric boundaries of some structures. The dimensions of these pockets of locally highly negative curvature are comparable to the size of a water molecule; the applicability of a continuum dielectric models in these regions is discussed. The maximum deviations from the NPB are reduced substantially when the boundary is smoothed by using a larger probe radius ͑3 Å͒ to generate the molecular surface. A detailed accuracy analysis is presented for several proteins of various shapes, including lysozyme whose surface features a functionally relevant region of negative curvature. The proposed analytical model is computationally inexpensive; this strength of the approach is demonstrated by computing and analyzing the electrostatic potential generated by a full capsid of the tobacco ring spot virus at atomic resolution ͑500 000 atoms͒. An analysis of the electrostatic potential of the inner surface of the capsid reveals what might be a RNA binding pocket. These results are generated with the modest computational power of a desktop personal computer.

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“…Consistent with this observation, monovalent ions, which generally bind only weakly to RNA, can induce proper folding and activity in the small ribozymes [35, 57–58]. Nevertheless, because the three-dimensional structure of RNA can develop concentrated pockets of negative electrostatic potential (−15 to −20 kT/e in the major groove, as low as −100 kT/e at some metal-binding sites) [59], entropy favors stabilization of compact native folds by divalent metal ions at physiologic concentrations [56]. …”

Section: Interactions Between Metal Ions and The Small Ribozymesmentioning

confidence: 88%

“…This raises the interesting possibility that monovalent cations may help a ribozyme to find the correct minimum-energy native structure by destabilizing alternative misfolds, as was recently suggested for the HDV ribozyme [88] as well as for larger group I intron ribozymes [95–96]. Since very dense electronegative pockets can form within the tertiary structure of RNA [59], divalent and trivalent cations, with their high charge density and ability to bridge pairs of negatively charged phosphates, promote the folding of RNA particularly well. Their ability to form stable inner-sphere contacts with electronegative functional groups, while not conferring much additional stability compared to outer-sphere electrostatic screening, has been proposed to make a larger range of backbone conformations available to RNA [56].…”

Section: Roles Of Metal Ions In Small Ribozymesmentioning

confidence: 99%

6 Metal Ions: Supporting Actors in the Playbook of Small Ribozymes

Johnson-Buck¹,

McDowell²,

Walter³

2015

Structural and Catalytic Roles of Metal Ions in RNA

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Since the 1980s, several small RNA motifs capable of chemical catalysis have been discovered. These small ribozymes, composed of between approximately 40 and 200 nucleotides, have been found to play vital roles in the replication of subviral and viral pathogens, gene regulation in prokaryotes, and have recently been discovered in noncoding eukaryotic RNAs. All of the known natural small ribozymes – the hairpin, hammerhead, hepatitis delta virus, Varkud satellite, and glmS ribozymes – catalyze the same self-cleavage reaction as RNAse A, resulting in two products, one bearing a 2′–3′ cyclic phosphate and the other a 5′-hydroxyl group. Although originally thought to be obligate metalloenzymes like the group I and II self-splicing introns, the small ribozymes are now known to support catalysis in a wide variety of cations that appear to be only indirectly involved in catalysis. Nevertheless, under physiologic conditions, metal ions are essential for the proper folding and function of the small ribozymes, the most effective of these being magnesium. Metal ions contribute to catalysis in the small ribozymes primarily by stabilizing the catalytically active conformation, but in some cases also by activating RNA functional groups for catalysis, directly participating in catalytic acid-base chemistry, and perhaps by neutralizing the developing negative charge of the transition state. Although interactions between the small ribozymes and cations are relatively nonspecific, ribozyme activity is quite sensitive to the types and concentrations of metal ions present in solution, suggesting a close evolutionary relationship between cellular metal ion homeostasis and cation requirements of catalytic RNAs, and perhaps RNA in general.

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Untitled

Cited by 195 publications

References 43 publications

The electrostatic characteristics of G{middle dot}U wobble base pairs

The electrostatic characteristics of G{middle dot}U wobble base pairs

An analytical approach to computing biomolecular electrostatic potential. II. Validation and applications

6 Metal Ions: Supporting Actors in the Playbook of Small Ribozymes

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