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Computational Investigation of Bending Properties of RNA AUUCU, CCUG, CAG, and CUG Repeat Expansions Associated With Neuromuscular Disorders
Expansions of RNA AUUCU, CCUG, CAG, and CUG repeats cause spinocerebellar ataxia type 10, myotonic dystrophy type 2, Huntington’s disease, and myotonic dystrophy type 1, respectively. By performing extensive molecular dynamic simulations, we investigated the bending propensities and conformational l...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9037632/ https://www.ncbi.nlm.nih.gov/pubmed/35480881 http://dx.doi.org/10.3389/fmolb.2022.830161 |
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author | Taghavi, Amirhossein Yildirim, Ilyas |
author_facet | Taghavi, Amirhossein Yildirim, Ilyas |
author_sort | Taghavi, Amirhossein |
collection | PubMed |
description | Expansions of RNA AUUCU, CCUG, CAG, and CUG repeats cause spinocerebellar ataxia type 10, myotonic dystrophy type 2, Huntington’s disease, and myotonic dystrophy type 1, respectively. By performing extensive molecular dynamic simulations, we investigated the bending propensities and conformational landscapes adopted by 3×3, 2×2, and 1×1 internal loops observed in RNA AUUCU, CCUG, CAG, and CUG repeat expansions using model systems having biologically relevant repeat sizes. We show that the conformational variability experienced by these loops is more complex than previous reports where a variety of unconventional hydrogen bonds are formed. At the global scale, strong bending propensity was observed in r(AUUCU)(10), r(CCUG)(15), r(CAG)(20,) and r(CUG)(20,) and, to a lesser extent, in r(AUUCU)(4), r(CCUG)(10), r(CAG)(10), and r(CUG)(10). Furthermore, RNA CAG repeats exhibit a tendency toward bent states with more than 50% of observed conformations having bending angles greater than 50°, while RNA CUG repeats display relatively linear-like conformations with extremely bent conformations accounting for less than 25% of the observed structures. Conformations experienced by RNA AUUCU repeats are a combination of strongly bent and kinked structures. The bent states in RNA CCUG repeats mostly fall into the moderately bent category with a marginal ensemble experiencing extreme bending. The general pattern observed in all the bent structures indicates the collapse of the major groove width as the mechanical trigger for bending, which is caused by alteration of base pair step parameters at multiple locations along the RNA due to local distortions at the loop sites. Overextension is also observed in all the RNA repeats that is attributed to widening of the major groove width as well as undertwisting phenomenon. This information and the rich structural repository could be applied for structure based small molecule design targeting disease-causing RNAs. The bending propensities of these constructs, at the global level, could also have implications on how expanded RNA repeats interact with proteins. |
format | Online Article Text |
id | pubmed-9037632 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-90376322022-04-26 Computational Investigation of Bending Properties of RNA AUUCU, CCUG, CAG, and CUG Repeat Expansions Associated With Neuromuscular Disorders Taghavi, Amirhossein Yildirim, Ilyas Front Mol Biosci Molecular Biosciences Expansions of RNA AUUCU, CCUG, CAG, and CUG repeats cause spinocerebellar ataxia type 10, myotonic dystrophy type 2, Huntington’s disease, and myotonic dystrophy type 1, respectively. By performing extensive molecular dynamic simulations, we investigated the bending propensities and conformational landscapes adopted by 3×3, 2×2, and 1×1 internal loops observed in RNA AUUCU, CCUG, CAG, and CUG repeat expansions using model systems having biologically relevant repeat sizes. We show that the conformational variability experienced by these loops is more complex than previous reports where a variety of unconventional hydrogen bonds are formed. At the global scale, strong bending propensity was observed in r(AUUCU)(10), r(CCUG)(15), r(CAG)(20,) and r(CUG)(20,) and, to a lesser extent, in r(AUUCU)(4), r(CCUG)(10), r(CAG)(10), and r(CUG)(10). Furthermore, RNA CAG repeats exhibit a tendency toward bent states with more than 50% of observed conformations having bending angles greater than 50°, while RNA CUG repeats display relatively linear-like conformations with extremely bent conformations accounting for less than 25% of the observed structures. Conformations experienced by RNA AUUCU repeats are a combination of strongly bent and kinked structures. The bent states in RNA CCUG repeats mostly fall into the moderately bent category with a marginal ensemble experiencing extreme bending. The general pattern observed in all the bent structures indicates the collapse of the major groove width as the mechanical trigger for bending, which is caused by alteration of base pair step parameters at multiple locations along the RNA due to local distortions at the loop sites. Overextension is also observed in all the RNA repeats that is attributed to widening of the major groove width as well as undertwisting phenomenon. This information and the rich structural repository could be applied for structure based small molecule design targeting disease-causing RNAs. The bending propensities of these constructs, at the global level, could also have implications on how expanded RNA repeats interact with proteins. Frontiers Media S.A. 2022-04-11 /pmc/articles/PMC9037632/ /pubmed/35480881 http://dx.doi.org/10.3389/fmolb.2022.830161 Text en Copyright © 2022 Taghavi and Yildirim. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Molecular Biosciences Taghavi, Amirhossein Yildirim, Ilyas Computational Investigation of Bending Properties of RNA AUUCU, CCUG, CAG, and CUG Repeat Expansions Associated With Neuromuscular Disorders |
title | Computational Investigation of Bending Properties of RNA AUUCU, CCUG, CAG, and CUG Repeat Expansions Associated With Neuromuscular Disorders |
title_full | Computational Investigation of Bending Properties of RNA AUUCU, CCUG, CAG, and CUG Repeat Expansions Associated With Neuromuscular Disorders |
title_fullStr | Computational Investigation of Bending Properties of RNA AUUCU, CCUG, CAG, and CUG Repeat Expansions Associated With Neuromuscular Disorders |
title_full_unstemmed | Computational Investigation of Bending Properties of RNA AUUCU, CCUG, CAG, and CUG Repeat Expansions Associated With Neuromuscular Disorders |
title_short | Computational Investigation of Bending Properties of RNA AUUCU, CCUG, CAG, and CUG Repeat Expansions Associated With Neuromuscular Disorders |
title_sort | computational investigation of bending properties of rna auucu, ccug, cag, and cug repeat expansions associated with neuromuscular disorders |
topic | Molecular Biosciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9037632/ https://www.ncbi.nlm.nih.gov/pubmed/35480881 http://dx.doi.org/10.3389/fmolb.2022.830161 |
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