N2 - A brief introduction to RNA structure and function is offered, including recent exciting discoveries concerning RNA's starring roles in gene regulation. AB - A brief introduction to RNA structure and function is offered, including recent exciting discoveries concerning RNA's starring roles in gene regulation. RNA The cousin left behind becomes a star.
Computational Studies of RNA and DNA | SpringerLink
Abstract A brief introduction to RNA structure and function is offered, including recent exciting discoveries concerning RNA's starring roles in gene regulation. Fingerprint RNA. Graph theory. Gene expression.
Computational studies of RNA and DNA
RNA: The cousin left behind becomes a star. Springer Netherlands.
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Springer Netherlands, The algorithm uses a unique hierarchical classification network based on mutual information, thermodynamics and Watson-Crick base-pairedness to predict structures. In addition, we have developed a web-based application, CorreLogo, that uses mutual information derived from RNA sequence alignments to determine covariations amongst base-paired positions.
The algorithm includes a unique error measure and depicts results in 3D. We developed, CyloFold, a unique algorithm for predicting, from a single sequence, RNA secondary structures that may include pseudoknots. This algorithm utilizes a novel technique that approximates the potential for 3D steric clashes in the predicted structures, thus filtering out those structures from consideration. The algorithm has been shown to have high accuracy when compared to other algorithms of its type.
We developed web software based on a Bayesian statistical approach that estimates the accuracy of base pair formation from data derived from SHAPE Selective 2' - Hydroxyl Acylation analyzed by Primer Extension experiments. Improvements could be seen if a 2 or 3 base context was also taken into account. We also showed that other types of known interactions did not correlate well. This type of information is helpful in ultimately determining the secondary structure of RNAs. Studies indicate that RNA may enter intermediate conformational states that are key to its functionality.
These states may have a significant impact on gene expression. It is known that the biologically functional states of RNA molecules may not correspond to their minimum energy state, that kinetic barriers may exist that trap the molecule in a local minimum, that folding often occurs during transcription, and cases exist in which a molecule will transition between one or more functional conformations before reaching its native state. Thus, methods for simulating the folding pathways of an RNA molecule, including co-transcriptional folding, and locating significant intermediate states are important for the prediction of RNA structure and its associated function.
Examples include the potato spindle tuber viroid, the host-killing mechanism of Escherichia coli plasmid R1, the hepatitis delta virus, HIV, and the dengue virus. These computational results are consistent with those derived from biological experiments. In addition, novel structural interactions and important functional intermediate and native states have been predicted. These have led to further successful confirmatory experiments. This new methodology, which was applied to Drosophila genomes, is currently being applied to other genomes. A parallel version of the program was devised to speed-up processing and the algorithms also rely on fast indexing schemes and conservative statistical methods to determine highly significant interactions.
The methodology has found interesting interactions that are related to endogenous siRNAs, gene transport and genes related to morphogenesis. The structures examined include an RNA tetraloop where temperature-dependent denaturation of the tetraloop and the subsequent refolding to the original crystal structure were performed. A three-way junction from the core central domain of the 30S ribosomal subunit from Thermus thermophilus was explored. It has been experimentally determined that the intermolecular interactions between the three-way junction and the S15 ribosomal protein initiate the process of the assembly of the 30S ribosomal subunit.
By using molecular dynamics simulations we obtained insights into the conformational transitions of the junction associated with the binding of S We determined using, molecular dynamics simulations, the structural effects of utilizing new types of modified RNA nucleotides containing carbocyclic sugars that are constrained to north or south conformations C2' or C3' exo.
In addition, we showed using molecular dynamics simulations, how ions and flanking bases play a very important role in human immunodeficiency virus HIV kissing loop monomer conformations. These results correlate well and may explain in detail, experimental studies that indicate the importance of ions for HIV-1 dimerization.
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We have also examined the pseudoknot domain of telomerase. Molecular modeling and molecular dynamics of the pseudoknot domain, including its hairpin loop, were performed. Results indicated how the hairpin loop dynamics affected the opening and closing of the non-canonical U-U base pairs found in the stem. The opening suggested nucleation points for the formation of the pseudoknot. We have also examined the effect of dyskeratosis congenita DKC mutations in the loop and how they reduced the propensity for the opening of the stem by forming a relatively stable hydrogen bond network in the hairpin loop.
We studied the dynamical impact of the DKC mutations on the pseudoknot with the result that the pseudoknot became unstable while the hairpin form became more stable. We discovered and elucidated the 3D structures of new types of translational enhancers that are found in the 3' UTRs of the Turnip Crinkle Virus the first of its kind found and the Pea enation Mosaic Virus. The discovery of these structural elements has brought to light new mechanisms for translational enhancement in eukaryotic plant viruses that may have broader implications for understanding translational mechanisms in general.
This pseudoknot is involved in frameshifting and appears to be stabilized by a microRNA, a novel function for a microRNA. In addition, we have employed methods based on elastic network interpolation to reduce the computational costs related to RNA 3D dynamics. Three-dimensional dynamics trajectories can be determined using a reduced atom representation and given conformational states. Compute time can be reduced from weeks to hours using this approach.
Computational RNA Nanobiology RNA nanobiology represents a new modality for the development of nanodevices that have the potential for use in a number of areas, including therapeutics. Building on our experience as outlined above, we developed several computational and experimental techniques see below that provide a means to determine a set of nucleotide sequences that can assemble into desired nano complexes. One of these tools is a relational database called RNAJunction.
Computational studies of RNA and DNA (Challenges and
The database contains structure and sequence information for known RNA helical junctions and kissing loop interactions. These motifs can be searched for in a variety of ways, providing a source for RNA nano building blocks. Another computational tool, NanoTiler, permits a user to construct specified RNA-based nanoscale shapes. NanoTiler provides a 3D graphical view of the objects being designed and provides the means to work interactively or with computer scripts on the design process even though the precise RNA sequences may not yet be specified, and an all-atom model is not available.
Also, a combinatorial search can be applied to enumerate structures that would not normally be considered.
Another web-based software tool for RNA nanostructure design is NanoFolder, which is one of the few software tools that are capable of predicting the structure and sequence attributes of multi-stranded RNA constructs. With this software it is possible to specify the desired secondary structure motifs and have the software predict the set of sequences that generate these desired motifs with the correct intra- and inter-strand folding characteristics. Experimental RNA Nanobiology Based on the above described computational approaches to RNA nanodesign we have demonstrated the ability to experimentally self-assemble and functionalize several RNA-based nanoparticles.
This was accomplished with close interactions between the experimental and computational approaches leading to enhancements to both sets of methodologies. Examples include the self-assembly of 6 and 10 stranded cubes; the self-assembly of hexagonal rings of various sizes and double rings utilizing an RNA motif extracted from nature; the modification of sequences in the motif to improve yield while also maintaining appropriate geometries; and the self-assembly of triangular structures.
We also developed techniques that define self-assembly protocols and that allow for co-transcriptional assembly of constructs that can also include modified bases to increase the chemical stability of these nanoparticles. In addition, we have functionalized these particles with up to six different siRNAs to enable controlled stoichiometry and gene silencing, and showed that these particles do indeed silence the designated genes when transfected into various cell lines.