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Force-dependent hopping rates of RNA hairpins can be estimated from accurate measurement of the folding landscapes.

ABSTRACT: The sequence-dependent folding landscapes of nucleic acid hairpins reflect much of the complexity of biomolecular folding. Folding trajectories, generated by using single-molecule force-clamp experiments by attaching semiflexible polymers to the ends of hairpins, have been used to infer their folding landscapes. Using simulations and theory, we study the effect of the dynamics of the attached handles on the handle-free RNA free-energy profile F(o)(eq)(z(m)), where z(m) is the molecular extension of the hairpin. Accurate measurements of F(o)(eq)(z(m)) requires stiff polymers with small L/l(p), where L is the contour length of the handle, and l(p) is the persistence length. Paradoxically, reliable estimates of the hopping rates can only be made by using flexible handles. Nevertheless, we show that the equilibrium free-energy profile F(o)(eq)(z(m)) at an external tension f(m), the force (f) at which the folded and unfolded states are equally populated, in conjunction with Kramers' theory, can provide accurate estimates of the force-dependent hopping rates in the absence of handles at arbitrary values of f. Our theoretical framework shows that z(m) is a good reaction coordinate for nucleic acid hairpins under tension.

SUBMITTER: Hyeon C

PROVIDER: S-EPMC2474478 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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Force-dependent hopping rates of RNA hairpins can be estimated from accurate measurement of the folding landscapes.

Hyeon Changbong C Morrison Greg G Thirumalai D D

Proceedings of the National Academy of Sciences of the United States of America 20080710 28

The sequence-dependent folding landscapes of nucleic acid hairpins reflect much of the complexity of biomolecular folding. Folding trajectories, generated by using single-molecule force-clamp experiments by attaching semiflexible polymers to the ends of hairpins, have been used to infer their folding landscapes. Using simulations and theory, we study the effect of the dynamics of the attached handles on the handle-free RNA free-energy profile F(o)(eq)(z(m)), where z(m) is the molecular extension ...[more]

PMID: 18621721

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Project description:MotivationThe function of an RNA molecule is not only linked to its native structure, which is usually taken to be the ground state of its folding landscape, but also in many cases crucially depends on the details of the folding pathways such as stable folding intermediates or the timing of the folding process itself. To model and understand these processes, it is necessary to go beyond ground state structures. The study of rugged RNA folding landscapes holds the key to answer these questions. Efficient coarse-graining methods are required to reduce the intractably vast energy landscapes into condensed representations such as barrier trees or basin hopping graphs : BHG) that convey an approximate but comprehensive picture of the folding kinetics. So far, exact and heuristic coarse-graining methods have been mostly restricted to the pseudoknot-free secondary structures. Pseudoknots, which are common motifs and have been repeatedly hypothesized to play an important role in guiding folding trajectories, were usually excluded.ResultsWe generalize the BHG framework to include pseudoknotted RNA structures and systematically study the differences in predicted folding behavior depending on whether pseudoknotted structures are allowed to occur as folding intermediates or not. We observe that RNAs with pseudoknotted ground state structures tend to have more pseudoknotted folding intermediates than RNAs with pseudoknot-free ground state structures. The occurrence and influence of pseudoknotted intermediates on the folding pathway, however, appear to depend very strongly on the individual RNAs so that no general rule can be inferred.Availability and implementationThe algorithms described here are implemented in C++ as standalone programs. Its source code and Supplemental material can be freely downloaded from http://www.tbi.univie.ac.at/bhg.html.Contactqin@bioinf.uni-leipzig.deSupplementary informationSupplementary data are available at Bioinformatics online.

Dataset Information

Force-dependent hopping rates of RNA hairpins can be estimated from accurate measurement of the folding landscapes.

Publications

Force-dependent hopping rates of RNA hairpins can be estimated from accurate measurement of the folding landscapes.

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