Phosphorothioate Substitutions in RNA Structure Studied by Molecular Dynamics Simulations, QM/MM Calculations, and NMR Experiments
| Autor: | Klaudia Mráziková, Jiří Šponer, Miroslav Krepl, Jennifer Vögele, Xiaohui Cang, Zhengyue Zhang, Holger Kruse, Jens Wöhnert |
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| Rok vydání: | 2021 |
| Předmět: |
Riboswitch
RNA Stability Magnetic Resonance Spectroscopy 010304 chemical physics Chemistry Stacking Hydrogen Bonding Electronic structure Nuclear magnetic resonance spectroscopy Molecular Dynamics Simulation 010402 general chemistry 01 natural sciences Phosphates 0104 chemical sciences Surfaces Coatings and Films QM/MM symbols.namesake Molecular dynamics Chemical physics 0103 physical sciences Materials Chemistry symbols RNA Physical and Theoretical Chemistry van der Waals force |
| Zdroj: | The Journal of Physical Chemistry B |
| ISSN: | 1520-5207 1520-6106 |
| Popis: | Phosphorothioates (PTs) are important chemical modifications of the RNA backbone where a single non-bridging oxygen of the phosphate is replaced with a sulphur atom. PT can stabilize RNAs by protecting them from hydrolysis and is commonly used as tool to explore their function. It is, however, unclear what basic physical effects PT has on RNA stability and electronic structure. Here, we present Molecular Dynamics (MD) simulations, quantum mechanical (QM) calculations, and NMR spectroscopy measurements, exploring the effects of PT modifications in the structural context of the Neomycin-sensing riboswitch (NSR). The NSR is the smallest biologically functional riboswitch with a well-defined structure stabilized by a U-turn motif. Three of the signature interactions of the U-turn; an H-bond, an anion-π interaction and a potassium binding site; are formed by RNA phosphates, making the NSR an ideal model for studying how PT affects RNA structure and dynamics. By comparing with high-level QM calculations, we reveal the distinct physical properties of the individual interactions facilitated by the PT. The sulphur substitution, besides weakening the direct H-bond interaction, reduces the directionality of H-bonding while increasing its dispersion and induction components. It also reduces the induction and increases dispersion component of the anion-π stacking. The sulphur force-field parameters commonly employed in the literature do not reflect these distinctions, leading to unsatisfactory description of PT in simulations of the NSR. We show that it is not possible to accurately describe the PT interactions using one universal set of van der Waals sulphur parameters and provide suggestions for improving the force-field performance. |
| Databáze: | OpenAIRE |
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