Computer Folding of RNA Tetraloops: Identification of Key Force Field Deficiencies

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.

arXiv commentReprinted with permission from J. Chem. Theory Comput. 2016, 12 (9), pp 4534-4548. Copyright 2016 American Chemical Society

References in corpus (7)

• Escaping free-energy minima
• Well-Tempered Metadynamics: A Smoothly Converging and Tunable Free-Energy Method
• PLUMED: a portable plugin for free-energy calculations with molecular dynamics
• Enhanced Sampling in Molecular Dynamics Using Metadynamics, Replica-Exchange, and Temperature-Acceleration
• The Role of Nucleobase Interactions in RNA Structure and Dynamics
• A simple bootstrap method for constructing nonparametric confidence bands for functions
• Non-specific binding of Na${}^{+}$ and Mg${}^{2+}$ to RNA determined by force spectroscopy methods

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• Combining simulations and solution experiments as a paradigm for RNA force field refinement
• Free Energy Landscape of GAGA and UUCG RNA Tetraloops
• Exploring RNA structure and dynamics through enhanced sampling simulations
• The mechanism of RNA base fraying: molecular dynamics simulations analyzed with core-set Markov state models
• Effects and limitations of a nucleobase-driven backmapping procedure for nucleic acids using steered Molecular Dynamics
• Automatic learning of hydrogen-bond fixes in an AMBER RNA force field