The theory of helix-based RNA folding kinetics and its application

RNAs carry out diverse biological functions, partly because different conformations of the same RNA sequence can play different roles in cellular activities. To fully understand the biological functions of RNAs requires a conceptual framework to investigate the folding kinetics of RNA molecules, instead of native structures alone. Over the past several decades, many experimental and theoretical methods have been developed to address RNA folding. The helix-based RNA folding theory is the one which uses helices as building blocks, to calculate folding kinetics of secondary structures with pseudoknots of long RNA in two different folding scenarios. Here, we will briefly review the helix-based RNA folding theory and its application in exploring regulation mechanisms of several riboswitches and self-cleavage activities of the hepatitis delta virus (HDV) ribozyme.

Specificity of mRNA Folding and Its Association with Evolutionarily Adaptive mRNA Secondary Structures

The secondary structure is a fundamental feature of both non-coding RNAs(ncRNAs)and messenger RNAs(mRNAs).However,our understanding of the secondary structures of mRNAs,especially those of the coding regions,remains elusive,likely due to translation and the lack of RNA-binding proteins that sustain the consensus structure like those binding to ncRNAs.Indeed,mRNAs have recently been found to adopt diverse alternative structures,but the overall functional significance remains untested.We hereby approach this problem by estimating the folding specificity,i.e.,the probability that a fragment of an mRNA folds back to the same partner once refolded.We show that the folding specificity of mRNAs is lower than that of ncRNAs and exhibits moderate evolutionary conservation.Notably,we find that specific rather than alternative folding is likely evolutionarily adaptive since specific folding is frequently associated with functionally important genes or sites within a gene.Additional analysis in combination with ribosome density suggests the ability to modulate ribosome movement as one potential functional advantage provided by specific folding.Our findings reveal a novel facet of the RNA structurome with important functional and evolutionary implications and indicate a potential method for distinguishing the mRNA secondary structures maintained by natural selection from molecular noise.

A study of different annealing schedules in SARNA-predict A permutation based SA algorithm for RNA folding

Purpose–The purpose of this paper is to present a study of the effect of different types of annealing schedules for a ribonucleic acid(RNA)secondary structure prediction algorithm based on simulated annealing(SA).Design/methodology/approach–An RNA folding algorithm was implemented that assembles the final structure from potential substructures(helixes).Structures are encoded as a permutation of helixes.An SA searches this space of permutations.Parameters and annealing schedules were studied and fine-tuned to optimize algorithm performance.Findings–In comparing with mfold,the SA algorithm shows comparable results(in terms of F-measure)even with a less sophisticated thermodynamic model.In terms of average specificity,the SA algorithm has provided surpassing results.Research limitations/implications–Most of the underlying thermodynamic models are too simplistic and incomplete to accurately model the free energy for larger structures.This is the largest limitation of free energy-based RNA folding algorithms in general.Practical implications–The algorithm offers a different approach that can be used in practice to fold RNA sequences quickly.Originality/value–The algorithm is one of only two SA-based RNA folding algorithms.The authors use a very different encoding,based on permutation of candidate helixes.The in depth study of annealing schedules and other parameters makes the algorithm a strong contender.Another benefit is that new thermodynamic models can be incorporated with relative ease(which is not the case for algorithms based on dynamic programming).

Molecular Phylogenetics and Functional Evolution of Major RNA Recognition Domains of Recently Cloned and Characterized Autoimmune RNA-Binding Particle

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are spliceosomal macromole-cular assemblages and thus actively participate in pre-mRNA metabolism. They are composed of evolutionary conserved and tandemly repeated motifs, where both RNA-binding and protein-protein recognition occur to achieve cellular activities. By yet unknown mechanisms, these ribonucleoprotein (RNP) particles are targeted by autoantibodies and hence play significant role in a variety of human systemic autoimmune diseases. This feature makes them important prognostic markers in terms of molecular epidemiology and pathogenesis of autoimmunity. Since RNP domain is one of the most conserved and widespread scaffolds, evolutionary analyses of these RNA-binding domains can provide further clues on disease-specific epitope formation. The study presented herein represents a sequence comparison of RNA-recognition regions of recently cloned and characterized human hnRNP A3 with those of other relevant hnRNP A/B-type proteins. Their implications in human autoimmunity are particularly emphasized.

Quantum conformational transition in biological macromolecule

Background： Recently we proposed a quantum theory on the conformational change of biomolecule, deduced several equations on protein folding rate from the first principles and discussed the experimental tests of the theory. The article is a review of these works. Methods： Based on the general equation of the conformation-transitional rate several theoretical results are deduced and compared with experimental data through bioinformatics methods. Results： The temperature dependence and the denaturant concentration dependence of the protein folding rate are deduced and compared with experimental data. The quantitative relation between protein folding rate and torsional mode number （or chain length） is deduced and the obtained formula can be applied to RNA folding as well. The quantum transition theory of two-state protein is successfully generalized to multi-state protein folding. Then, how to make direct experimental tests on the quantum property of the conformational transition of biomolecule is discussed, which includes the study of protein photo-folding and the observation of the fluctuation of the fluorescence intensity emitted from the protein folding/unfolding event. Finally, the potential applications of the present quantum folding theory to molecular biological problems are sketched in two examples： the glucose transport across membrane and the induced pluripotency in stem cell. Conclusions： The above results show that the quantum mechanics provides a unifying and logically simple theoretical starting point in studying the conformational change of biological macromoleeules. The far-reachlng results in practical application of the theory are expected.