Molecular dynamics simulations reveal the parallel stranded d (GGGA)3GGG DNA quadruplex folds via multiple paths from a coil-like ensemble

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F24%3A00584664" target="_blank" >RIV/68081707:_____/24:00584664 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61989100:27740/24:10254885

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0141813024005154?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0141813024005154?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ijbiomac.2024.129712" target="_blank" >10.1016/j.ijbiomac.2024.129712</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Molecular dynamics simulations reveal the parallel stranded d (GGGA)3GGG DNA quadruplex folds via multiple paths from a coil-like ensemble

Popis výsledku v původním jazyce

G-quadruplexes (G4s) are non-canonical nucleic acid structures that fold through complex processes. Characterization of the G4 folding landscape may help to elucidate biological roles of G4s but is challenging both experimentally and computationally. Here, we achieved complete folding of a three-quartet parallel DNA G4 with (GGGA)3GGG sequence using all-atom explicit-solvent enhanced-sampling molecular dynamics (MD) simulations. The simulations suggested early formation of guanine stacks in the G-tracts, which behave as semi-rigid blocks in the folding process. The folding continues via the formation of a collapsed compact coil-like ensemble. Structuring of the G4 from the coil then proceeds via various cross-like, hairpin, slip-stranded and two-quartet ensembles and can bypass the G-triplex structure. Folding of the parallel G4 does not appear to involve any salient intermediates and is a multi-pathway process. We also carried out an extended set of simulations of parallel G-hairpins. While parallel G-hairpins are extremely unstable when isolated, they are more stable inside the coil structure. On the methodology side, we show that the AMBER DNA force field predicts the folded G4 to be less stable than the unfolded ensemble, uncovering substantial force-field issues. Overall, we provide unique atomistic insights into the folding landscape of parallel-stranded G4 but also reveal limitations of current state-ofthe-art MD techniques.

Název v anglickém jazyce

Molecular dynamics simulations reveal the parallel stranded d (GGGA)3GGG DNA quadruplex folds via multiple paths from a coil-like ensemble

Popis výsledku anglicky

G-quadruplexes (G4s) are non-canonical nucleic acid structures that fold through complex processes. Characterization of the G4 folding landscape may help to elucidate biological roles of G4s but is challenging both experimentally and computationally. Here, we achieved complete folding of a three-quartet parallel DNA G4 with (GGGA)3GGG sequence using all-atom explicit-solvent enhanced-sampling molecular dynamics (MD) simulations. The simulations suggested early formation of guanine stacks in the G-tracts, which behave as semi-rigid blocks in the folding process. The folding continues via the formation of a collapsed compact coil-like ensemble. Structuring of the G4 from the coil then proceeds via various cross-like, hairpin, slip-stranded and two-quartet ensembles and can bypass the G-triplex structure. Folding of the parallel G4 does not appear to involve any salient intermediates and is a multi-pathway process. We also carried out an extended set of simulations of parallel G-hairpins. While parallel G-hairpins are extremely unstable when isolated, they are more stable inside the coil structure. On the methodology side, we show that the AMBER DNA force field predicts the folded G4 to be less stable than the unfolded ensemble, uncovering substantial force-field issues. Overall, we provide unique atomistic insights into the folding landscape of parallel-stranded G4 but also reveal limitations of current state-ofthe-art MD techniques.

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/GA21-23718S" target="_blank" >GA21-23718S: Studium fascinující fyzikální chemie DNA pomocí pokročilých výpočetních metod</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2024

Kód důvěrnosti údajů

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

Název periodika

International Journal of Biological Macromolecules

ISSN

0141-8130

e-ISSN

1879-0003

Svazek periodika

261

Číslo periodika v rámci svazku

2024-03-22

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

15

Strana od-do

129712

Kód UT WoS článku

001176500400001

EID výsledku v databázi Scopus

2-s2.0-85183987821