Complex RNA Folding Kinetics Revealed by Single-Molecule FRET and Hidden Markov Models
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We have developed a hidden Markov model and optimization procedure for photon-based single-molecule FRET data, which takes into account the trace-dependent background intensities. This analysis technique reveals an unprecedented amount of detail in the folding kinetics of the Diels-Alderase ribozyme. We find a multitude of extended (low-FRET) and compact (high-FRET) states. Five states were consistently and independently identified in two FRET constructs and at three Mg(2+) concentrations. Structures generally tend to become more compact upon addition of Mg(2+). Some compact structures are observed to significantly depend on Mg(2+) concentration, suggesting a tertiary fold stabilized by Mg(2+) ions. One compact structure was observed to be Mg(2+)-independent, consistent with stabilization by tertiary Watson-Crick base pairing found in the folded Diels-Alderase structure. A hierarchy of time scales was discovered, including dynamics of 10 ms or faster, likely due to tertiary structure fluctuations, and slow dynamics on the seconds time scale, presumably associated with significant changes in secondary structure. The folding pathways proceed through a series of intermediate secondary structures. There exist both compact pathways and more complex ones, which display tertiary unfolding, then secondary refolding, and, subsequently, again tertiary refolding.
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The complex MSM obtained from single-molecule FRET studies of the Diels-Alderase ribozyme permitted the use of transition path theory and transition matrix eigenvector analysis for describing the Mg2+-dependent folding pathway.
“The complex MSM obtained from single-molecule FRET studies of the Diels-Alderase ribozyme permitted the use of transition path theory and transition matrix eigenvector analysis for describing the Mg2+-dependent folding pathway [77].”
From Markov state models of biomolecular conformational dynamics (2014) · cites this paper as [77]
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Accuracy of maximum likelihood estimates of a two-state model in single-molecule FRET
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Using sm-FRET and Denaturants to Reveal Folding Landscapes
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Application of Hidden Markov Models in Biomolecular Simulations
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RNA as a Complex Polymer with Coupled Dynamics of Ions and Water in the Outer Solvation Sphere
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Statistical Methodology in Single-Molecule Experiments
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Dynamical matrix propagator scheme for large-scale proton dynamics simulations.
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Fast Folding Dynamics of an Intermediate State in RNase H Measured by Single-Molecule FRET
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Self-citationDissection of Interaction Kinetics through Single-Molecule Interaction Simulation
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A flexible approach to assess fluorescence decay functions in complex energy transfer systems
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Exploring the energy landscape of a SAM-I riboswitch
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Putting Humpty–Dumpty Together
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Theory and Analysis of Single-Molecule FRET Experiments
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Structure and Mechanical Stabilities of the Three-Way Junction Motifs in Prohead RNA
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Rapid single‐molecule imaging in cyclic olefin copolymer channels
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Exploring RNA Conformational Ensembles In Silico: Progress and Challenges
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A Continuous Time Representation of smFRET for the Extraction of Rapid KineticsPreprint
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Advanced Approaches to Diagnose and Treat the Chronic Autoimmune Disorders
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FRETtranslator: translating FRET traces into RNA structural pathwaysPreprint
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Experiment-friendly kinetic analysis of single molecule data in and out of equilibriumPreprint
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- Authors
- Keller, B. G., Kobitski, A., Jäschke, A., Nienhaus, G. U., & Noé, F.
- Affiliations
- Freie Universität Berlin (DE)
- Karlsruhe Institute of Technology (DE)
- Heidelberg University (DE)
- Corresponding author
- Keller, Bettina G.
- Noé, Frank
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2014-03-14
- Volume
- 136
- Issue
- 12
- Pages
- 4534-4543
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- PMC
- PMC3977575
- OpenAlex
- W1975720346
- Cited by
- 84
- References
- 53
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 4 · 2022: 5 · 2021: 8 · 2020: 8 · 2019: 5 · 2018: 9 · 2017: 7 · 2016: 15 · 2015: 8 · 2014: 9
- FWCI
- 5.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of the American Chemical Society (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Research Council (pc-Cell)
- Deutsche Forschungsgemeinschaft (NI 291/9, NO 825/2, JA 794/3)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- RNA folding kinetics, single-molecule FRET, hidden Markov models, Mg2+ concentration, protein tertiary structure, Watson-Crick base pairing, folding intermediates, folding pathways, conformational dynamics
- MeSH terms
- Base Sequence, Kinetics, Markov Chains, Models, Molecular, Nucleic Acid Conformation, RNA, Catalytic, Fluorescence Resonance Energy Transfer, RNA Folding
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