https://dx.doi.org/10.1021/acs.jctc.0c01199">
 

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Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

Abstract

Base flipping is a key biophysical event involved in recognition of various ligands by ribonucleic acid (RNA) molecules. However, the mechanism of base flipping in RNA remains poorly understood, in part due to the lack of atomistic details on complex rearrangements in neighboring bases. In this work, we applied transition path sampling (TPS) methods to study base flipping in a double-stranded RNA (dsRNA) molecule that is known to interact with RNA-editing enzymes through this mechanism. We obtained an ensemble of 1000 transition trajectories to describe the base-flipping process. We used the likelihood maximization method to determine the refined reaction coordinate (RC) consisting of two collective variables (CVs), a distance and a dihedral angle between nucleotides that form stacking interactions with the flipping base. The free energy profile projected along the refined RC revealed three minima, two corresponding to the initial and final states and one for a metastable state. We suggest that the metastable state likely represents a wobbled conformation of nucleobases observed in NMR studies that is often characterized as the flipped state. The analyses of reactive trajectories further revealed that the base flipping is coupled to a global conformational change in a stem-loop of dsRNA.

Publication Date

2-17-2021

Publisher

ACS Publications

Journal Title

Journal of Chemical Theory and Computation

Digital Object Identifier (DOI)

https://dx.doi.org/10.1021/acs.jctc.0c01199

Document Type

Article

Rights

Copyright © 2021 The Authors. Published by American Chemical Society

Comments

This is an Open Access article published by ACS Publications in Journal of Chemical Theory and Computation in 2021, available online: https://dx.doi.org/10.1021/acs.jctc.0c01199

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