RNA G-quadruplexes emerge from a compacted coil-like ensemble via multiple pathways

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F25%3A00639192" target="_blank" >RIV/68081707:_____/25:00639192 - isvavai.cz</a>

Výsledek na webu

<a href="https://academic.oup.com/nar/article/53/17/gkaf872/8249853" target="_blank" >https://academic.oup.com/nar/article/53/17/gkaf872/8249853</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1093/nar/gkaf872" target="_blank" >10.1093/nar/gkaf872</a>

Jazyk výsledku

angličtina

Název v původním jazyce

RNA G-quadruplexes emerge from a compacted coil-like ensemble via multiple pathways

Popis výsledku v původním jazyce

RNA G-quadruplexes (rG4s) are emerging as vital structural elements involved in processes like gene regulation, translation, and genome stability. Found in untranslated regions of messenger RNAs (mRNAs), they influence translation efficiency and mRNA localization. Additionally, rG4s of long noncoding RNAs and telomeric RNA play roles in RNA processing and cellular aging. Despite their significance, the atomic-level folding mechanisms of rG4s remain poorly understood due to their complexity. We studied the folding of the r(GGGA)3GGG and r(GGGUUA)3GGG (TERRA) sequences into parallel-stranded rG4 using all-atom enhanced-sampling molecular dynamics simulations, applying well-tempered metadynamics coupled with solute tempering. The obtained folding pathways suggest that RNA initially adopts a compacted coil-like ensemble characterized by dynamic guanine stacking and pairing. The three-quartet rG4 gradually forms from this compacted coil ensemble via diverse routes involving strand rearrangements and guanine incorporations. While the folding mechanism is multipathway, various two-quartet rG4 structures appear to be a common transitory ensemble along most routes. Thus, the process seems more complex than previously predicted, as G-hairpins or G-triplexes do not act as distinct intermediates, even though some are occasionally sampled. We also discuss the challenges of applying enhanced sampling methodologies to such a multidimensional free-energy surface and address the force-field limitations.

Název v anglickém jazyce

RNA G-quadruplexes emerge from a compacted coil-like ensemble via multiple pathways

Popis výsledku anglicky

RNA G-quadruplexes (rG4s) are emerging as vital structural elements involved in processes like gene regulation, translation, and genome stability. Found in untranslated regions of messenger RNAs (mRNAs), they influence translation efficiency and mRNA localization. Additionally, rG4s of long noncoding RNAs and telomeric RNA play roles in RNA processing and cellular aging. Despite their significance, the atomic-level folding mechanisms of rG4s remain poorly understood due to their complexity. We studied the folding of the r(GGGA)3GGG and r(GGGUUA)3GGG (TERRA) sequences into parallel-stranded rG4 using all-atom enhanced-sampling molecular dynamics simulations, applying well-tempered metadynamics coupled with solute tempering. The obtained folding pathways suggest that RNA initially adopts a compacted coil-like ensemble characterized by dynamic guanine stacking and pairing. The three-quartet rG4 gradually forms from this compacted coil ensemble via diverse routes involving strand rearrangements and guanine incorporations. While the folding mechanism is multipathway, various two-quartet rG4 structures appear to be a common transitory ensemble along most routes. Thus, the process seems more complex than previously predicted, as G-hairpins or G-triplexes do not act as distinct intermediates, even though some are occasionally sampled. We also discuss the challenges of applying enhanced sampling methodologies to such a multidimensional free-energy surface and address the force-field limitations.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/EF15_003%2F0000477" target="_blank" >EF15_003/0000477: Strukturní gymnastika nukleových kyselin: od molekulárních principů přes biologické funkce k terapeutickým cílům.</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Nucleic Acids Research

ISSN

0305-1048

e-ISSN

1362-4962

Svazek periodika

53

Číslo periodika v rámci svazku

17

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

16

Strana od-do

gkaf872

Kód UT WoS článku

001566462300001

EID výsledku v databázi Scopus

2-s2.0-105015556322