Small Details Matter: The 2′-Hydroxyl as a Conformational Switch in RNA

Abstract

While DNA is mostly a primary carrier of genetic information and displays a regular duplex structure, RNA can form very complicated and conserved 3D structures displaying a large variety of functions, such as being an intermediary carrier of the genetic information, translating such information into the protein machinery of the cell, or even acting as a chemical catalyst. At the base of such functional diversity is the subtle balance between different backbone, nucleobase, and ribose conformations, finely regulated by the combination of hydrogen bonds and stacking interactions. Although an apparently simple chemical modification, the presence of the 2'OH in RNA has a profound effect in the ribonucleotide conformational balance, adding an extra layer of complexity to the interactions network in RNA. In the present work, we have combined database analysis with extensive molecular dynamics, quantum mechanics, and hybrid QM/MM simulations to provide direct evidence on the dramatic impact of the 2'OH conformation on sugar puckering. Calculations provide evidence that proteins can modulate the 2'OH conformation to drive sugar repuckering, leading then to the formation of bioactive conformations. In summary, the 2'OH group seems to be a primary molecular switch contributing to specific protein-RNA recognition.

RNA Structural Dynamics As Captured by Molecular Simulations: A Comprehensive Overview

“… 150 Bergonzo et al showed that using the larger, less hydrophilic phosphate groups described by these parameters yielded a better description of tetranucleotides 126 and tetraloops. 139 The Steinbrecher phosphate parameters were also used by Darré et al 151 in a different way, in conjunction with abandoning the Lorentz–Berthelot combination rules for the Lennard-Jones potential. The simulations showed a slightly better description of tetranucleotides than reported by Bergonzo et al 139 In addition, Darré et al modified also the torsional parameters of the C2′–OH group of ribose.…”

Polarizable force field for RNA based on the classical drude oscillator

“…These observations indicate that parameters related to sugar pucker and the 2 0 -hydroxyl orientation may require some refinement to better capture these effects, which are known to be coupled. [108] Stability of dsDNA using the updated Drude-2017 force field…”

Coming Together: RNAs and Proteins Assemble under the Single-Molecule Fluorescence Microscope

“…Labeling sites must be chosen so as to avoid influencing interactions between the RNA and its binding partner(s), or perturbing secondary or tertiary interactions within the RNA or its conformational dynamics (Al-Hashimi and Walter 2008;Mustoe et al 2014;Darre et al 2016). For example, 2 ′ modifications on the ribose sugar can alter the thermal stability of double-stranded regions (Hendrix et al 1995;Fauster et al 2012), whereas attachment of fluorophores at 5 ′ or 3 ′ termini can increase duplex stability through stacking of the fluorophores on the terminal base-pairs (Cisse et al 2012;Liu and Lilley 2017).…”