ArticleJournal of chemical theory and computation2016
Computer Folding of RNA Tetraloops: Identification of Key Force Field Deficiencies.
Article in Journal of chemical theory and computation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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57 citing papers in PubMed.
- From gHBfix to NBfix: Reweighting-Driven Refinement of Hydrogen-Bond Interactions in RNA Force Fields.Journal of chemical theory and computation · 2026Article
- Toward Accurate RNA Folding Thermodynamics: Evaluation of Enhanced Sampling Methods for Force Field Benchmarking.Journal of chemical theory and computation · 2026Article
- U2 snRNP recognizes the branch site through a loaded-spring strand-invasion mechanism.Nucleic acids research · 2026Article
- Destabilization of Structured RNAs by OPC and TIP4PD Water Models.Journal of chemical theory and computation · 2026Article
- Latent thermodynamic flows: unified representation learning and generative modeling of temperature-dependent behaviors from limited data.Chemical science · 2026Article
- Force fields matter in DNA polProtein science : a publication of the Protein Society · 2026Article
- The Kink-Turn 7 Motif: An Additional Test for RNA Force Field Performance.Journal of chemical theory and computation · 2025Article
- Molecular Dynamics Simulations of RNA Stem-Loop Folding Using an Atomistic Force Field and a Generalized Born Implicit Solvent.ACS omega · 2025Article
- DynaRNA: accurate dynamic RNA conformation ensemble generation with diffusion model.Communications biology · 2025Article
- Can We Ever Develop an Ideal RNA Force Field? Lessons Learned from Simulations of the UUCG RNA Tetraloop and Other Systems.Journal of chemical theory and computation · 2025Article
- Computational Methods for Modeling Lipid-Mediated Active Pharmaceutical Ingredient Delivery.Molecular pharmaceutics · 2025Review
- Inferring phase transitions and critical exponents from limited observations with thermodynamic maps.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Atomically resolved imaging of the conformations and adsorption geometries of individual β-cyclodextrins with non-contact AFM.Nature communications · 2024Article
- Supercomputing in the biological sciences: Toward Zettascale and Yottascale simulations.Current opinion in structural biology · 2024Review
- Comprehensive Assessment of Force-Field Performance in Molecular Dynamics Simulations of DNA/RNA Hybrid Duplexes.Journal of chemical theory and computation · 2024Article
- Accurately Modeling RNA Stem-Loops in an Implicit Solvent Environment.Journal of chemical information and modeling · 2024Article
- Assessing RNA atomistic force fields via energy landscape explorations in implicit solvent.Biophysical reviews · 2024Review
- Dynamics and Function of sRNA/mRNAs Under the Scrutiny of Computational Simulation Methods.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Simple Adjustment of Intranucleotide Base-Phosphate Interaction in the OL3 AMBER Force Field Improves RNA Simulations.Journal of chemical theory and computation · 2023Article
- RNA folding pathways from all-atom simulations with a variationally improved history-dependent bias.Biophysical journal · 2023Article
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7 authors.
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Abstract
The computer-aided folding of biomolecules, particularly RNAs, is one of the most difficult challenges in computational structural biology. RNA tetraloops are fundamental RNA motifs playing key roles in RNA folding and RNA-RNA and RNA-protein interactions. Although state-of-the-art Molecular Dynamics (MD) force fields correctly describe the native state of these tetraloops as a stable free-energy basin on the microsecond time scale, enhanced sampling techniques reveal that the native state is not the global free energy minimum, suggesting yet unidentified significant imbalances in the force fields. Here, we tested our ability to fold the RNA tetraloops in various force fields and simulation settings. We employed three different enhanced sampling techniques, namely, temperature replica exchange MD (T-REMD), replica exchange with solute tempering (REST2), and well-tempered metadynamics (WT-MetaD). We aimed to separate problems caused by limited sampling from those due to force-field inaccuracies. We found that none of the contemporary force fields is able to correctly describe folding of the 5'-GAGA-3' tetraloop over a range of simulation conditions. We thus aimed to identify which terms of the force field are responsible for this poor description of TL folding. We showed that at least two different imbalances contribute to this behavior, namely, overstabilization of base-phosphate and/or sugar-phosphate interactions and underestimated stability of the hydrogen bonding interaction in base pairing. The first artifact stabilizes the unfolded ensemble, while the second one destabilizes the folded state. The former problem might be partially alleviated by reparametrization of the van der Waals parameters of the phosphate oxygens suggested by Case et al., while in order to overcome the latter effect we suggest local potentials to better capture hydrogen bonding interactions.
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