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Watching ion-driven kinetics of ribozyme folding and misfolding caused by energetic and topological frustration one molecule at a time
Folding of ribozymes into well-defined tertiary structures usually requires divalent cations. How Mg(2+) ions direct the folding kinetics has been a long-standing unsolved problem because experiments cannot detect the positions and dynamics of ions. To address this problem, we used molecular simulat...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10602927/ https://www.ncbi.nlm.nih.gov/pubmed/37758176 http://dx.doi.org/10.1093/nar/gkad755 |
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author | Hori, Naoto Thirumalai, D |
author_facet | Hori, Naoto Thirumalai, D |
author_sort | Hori, Naoto |
collection | PubMed |
description | Folding of ribozymes into well-defined tertiary structures usually requires divalent cations. How Mg(2+) ions direct the folding kinetics has been a long-standing unsolved problem because experiments cannot detect the positions and dynamics of ions. To address this problem, we used molecular simulations to dissect the folding kinetics of the Azoarcus ribozyme by monitoring the path each molecule takes to reach the folded state. We quantitatively establish that Mg(2+) binding to specific sites, coupled with counter-ion release of monovalent cations, stimulate the formation of secondary and tertiary structures, leading to diverse pathways that include direct rapid folding and trapping in misfolded structures. In some molecules, key tertiary structural elements form when Mg(2+) ions bind to specific RNA sites at the earliest stages of the folding, leading to specific collapse and rapid folding. In others, the formation of non-native base pairs, whose rearrangement is needed to reach the folded state, is the rate-limiting step. Escape from energetic traps, driven by thermal fluctuations, occurs readily. In contrast, the transition to the native state from long-lived topologically trapped native-like metastable states is extremely slow. Specific collapse and formation of energetically or topologically frustrated states occur early in the assembly process. |
format | Online Article Text |
id | pubmed-10602927 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-106029272023-10-28 Watching ion-driven kinetics of ribozyme folding and misfolding caused by energetic and topological frustration one molecule at a time Hori, Naoto Thirumalai, D Nucleic Acids Res RNA and RNA-protein complexes Folding of ribozymes into well-defined tertiary structures usually requires divalent cations. How Mg(2+) ions direct the folding kinetics has been a long-standing unsolved problem because experiments cannot detect the positions and dynamics of ions. To address this problem, we used molecular simulations to dissect the folding kinetics of the Azoarcus ribozyme by monitoring the path each molecule takes to reach the folded state. We quantitatively establish that Mg(2+) binding to specific sites, coupled with counter-ion release of monovalent cations, stimulate the formation of secondary and tertiary structures, leading to diverse pathways that include direct rapid folding and trapping in misfolded structures. In some molecules, key tertiary structural elements form when Mg(2+) ions bind to specific RNA sites at the earliest stages of the folding, leading to specific collapse and rapid folding. In others, the formation of non-native base pairs, whose rearrangement is needed to reach the folded state, is the rate-limiting step. Escape from energetic traps, driven by thermal fluctuations, occurs readily. In contrast, the transition to the native state from long-lived topologically trapped native-like metastable states is extremely slow. Specific collapse and formation of energetically or topologically frustrated states occur early in the assembly process. Oxford University Press 2023-09-27 /pmc/articles/PMC10602927/ /pubmed/37758176 http://dx.doi.org/10.1093/nar/gkad755 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | RNA and RNA-protein complexes Hori, Naoto Thirumalai, D Watching ion-driven kinetics of ribozyme folding and misfolding caused by energetic and topological frustration one molecule at a time |
title | Watching ion-driven kinetics of ribozyme folding and misfolding caused by energetic and topological frustration one molecule at a time |
title_full | Watching ion-driven kinetics of ribozyme folding and misfolding caused by energetic and topological frustration one molecule at a time |
title_fullStr | Watching ion-driven kinetics of ribozyme folding and misfolding caused by energetic and topological frustration one molecule at a time |
title_full_unstemmed | Watching ion-driven kinetics of ribozyme folding and misfolding caused by energetic and topological frustration one molecule at a time |
title_short | Watching ion-driven kinetics of ribozyme folding and misfolding caused by energetic and topological frustration one molecule at a time |
title_sort | watching ion-driven kinetics of ribozyme folding and misfolding caused by energetic and topological frustration one molecule at a time |
topic | RNA and RNA-protein complexes |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10602927/ https://www.ncbi.nlm.nih.gov/pubmed/37758176 http://dx.doi.org/10.1093/nar/gkad755 |
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