The Chirality of a Four-Way Helical Junction in RNA

Goody, Terry A.; Lilley, David M. J.; Norman, D.

doi:10.1021/ja0319240

Cited by 13 publications

(10 citation statements)

References 25 publications

(40 reference statements)

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“…Our results indicate that a right-handed antiparallel conformation is most consistent with the FRET data. Subsequent gel electrophoresis experiments showed that this four-way junction indeed prefers the right-handed antiparallel form (30).…”

Section: Application 2: Interpreting Limited Experimental Data With Mmentioning

confidence: 96%

Modeling and design by hierarchical natural moves

Sim

Levitt²,

Mináry³

2012

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

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We develop a unique algorithm implemented in the program MOSAICS (Methodologies for Optimization and Sampling in Computational Studies) that is capable of nanoscale modeling without compromising the resolution of interest. This is achieved by modeling with customizable hierarchical degrees of freedom, thereby circumventing major limitations of conventional molecular modeling. With the emergence of RNA-based nanotechnology, large RNAs in all-atom representation are used here to benchmark our algorithm. Our method locates all favorable structural states of a model RNA of significant complexity while improving sampling accuracy and increasing speed many fold over existing all-atom RNA modeling methods. We also modeled the effects of sequence mutations on the structural building blocks of tRNA-based nanotechnology. With its flexibility in choosing arbitrary degrees of freedom as well as in allowing different all-atom energy functions, MOSAICS is an ideal tool to model and design biomolecules of the nanoscale.hierarchical sampling | junctions | molecular simulation | Monte Carlo | nanostructure C omputational modeling is an important aspect of biology and nanotechnology. In silico design and manipulation of nanostructures often precedes experimental validation (1, 2), while effective computational structure prediction of biomolecules paves the way for biomolecular design (3). Most molecular modeling packages are either general but inefficient in modeling large molecular systems or designed to be effective for modeling only specific types of systems (e.g., coarse-grained modeling of DNA as an elastic rod) and are therefore not general purpose. These limitations are mainly a consequence of two major obstacles to computational modeling: (i) the high dimensionality of the systems studied and (ii) the complexity of the potential energy surface guiding the simulation. When attempting to model nanoscale systems at all-atom resolution, the combination of these two factors often leads to intractable complexity.A wide range of methods has been proposed to remove obstacles presented by high dimensionality (4-6) and complex energy surfaces (7-12), but none of these studies has considered both limitations in the same context. The difficulty of such a unified approach is that limitations arising from both obstacles are related in that reducing dimensionality often results in a more complex energy surface. For example, conformational sampling using dihedral angles, which is a common solution to the high dimensionality problem of macromolecular assemblies, often results in a more complex energy surface with energy barriers that could have been easily avoided in Cartesian space. The algorithm [implemented in MOSAICS (13)] proposed here overcomes the problem of high dimensionality without increasing the complexity of the underlying energy surface. This is achieved by sampling with hierarchical variables: Degrees of freedom that introduce large conformational changes are combined with degrees of freedom that allow for local rearrangeme...

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Section: Application 2: Interpreting Limited Experimental Data With Mmentioning

confidence: 96%

Modeling and design by hierarchical natural moves

Sim

Levitt²,

Mináry³

2012

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

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“…The mobility has been plotted against spacer length and fitted to a model based upon the Lumpkin–Zimm theory assuming bends of fixed angle and dihedral angle for both the A 5 bulge and the U1A box 2. ( b ) The four-way junction of the hairpin ribozyme (Goody et al 2004). The ribozyme junction was combined with an A 4 bulge with a variable length spacer of 8–22 bp between them.…”

Section: Bends and Kinks In Duplex Nucleic Acidsmentioning

confidence: 99%

Analysis of branched nucleic acid structure using comparative gel electrophoresis

Lilley

2008

Quart. Rev. Biophys.

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Electrophoresis in polyacrylamide gels provides a simple yet powerful means of analyzing the relative disposition of helical arms in branched nucleic acids. The electrophoretic mobility of DNA or RNA with a central discontinuity is determined by the angle subtended between the arms radiating from the branchpoint. In a multi-helical branchpoint, comparative gel electrophoresis can provide a relative measure of all the inter-helical angles and thus the shape and symmetry of the molecule. Using the long-short arm approach, the electrophoretic mobility of all the species with two helical arms that are longer than all others is compared. This can be done as a function of conditions, allowing the analysis of ion-dependent folding of branched DNA and RNA species. Notable successes for the technique include the four-way (Holliday) junction in DNA and helical junctions in functionally significant RNA species such as ribozymes. Many of these structures have subsequently been proved correct by crystallography or other methods, up to 10 years later in the case of the Holliday junction. Just as important, the technique has not failed to date. Comparative gel electrophoresis can provide a window on both fast and slow conformational equilibria such as conformer exchange in four-way DNA junctions. But perhaps the biggest test of the approach has been to deduce the structures of complexes of four-way DNA junctions with proteins. Two recent crystallographic structures show that the global structures were correctly deduced by electrophoresis, proving the worth of the method even in these rather complex systems. Comparative gel electrophoresis is a robust method for the analysis of branched nucleic acids and their complexes.

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“…37 Figure 9 reports the chirality values along Hammerhead ribozyme highlighting, as experimentally shown, [56][57][58] a fine regulation in the handedness of RNA junctions.…”

Section: Nucleosome and Ribosome Structuresmentioning

confidence: 81%

A quantitative measure of chirality inside nucleic acid databank

Pietropaolo

Parrinello

2011

Chirality

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We show the capability of a chirality index (Pietropaolo et al., Proteins 2008;70:667-677) to investigate nucleic acid structures because of its high sensitivity to helical conformations. By analyzing selected structures of DNA and RNA, we have found that sequences rich in cytosine and guanine have a tendency to left-handed chirality, in contrast to regions rich in adenine or thymine which show strong negative, right-handed, chirality values. We also analyze RNA structures, where specific loops and hairpin motifs are characterized by a well-defined chirality value. We find that in nucleosome the chirality is exalted, whereas in ribosome it is reduced. Our results illustrate the sensitivity of this descriptor for nucleic acid conformations.

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The Chirality of a Four-Way Helical Junction in RNA

Cited by 13 publications

References 25 publications

Modeling and design by hierarchical natural moves

Modeling and design by hierarchical natural moves

Analysis of branched nucleic acid structure using comparative gel electrophoresis

A quantitative measure of chirality inside nucleic acid databank

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