Insights into Stability and Folding of GNRA and UNCG Tetra
loops Revealed by Microsecond Molecular Dynamics and
Well-Tempered Metadynamics

J 2015

Insights into Stability and Folding of GNRA and UNCG Tetra loops Revealed by Microsecond Molecular Dynamics and Well-Tempered Metadynamics

HALDAR, Susanta; Petra KUHROVÁ; Pavel BANÁŠ; Vojtěch SPIWOK; Jiří ŠPONER et. al.

Základní údaje

Originální název

Insights into Stability and Folding of GNRA and UNCG Tetra loops Revealed by Microsecond Molecular Dynamics and Well-Tempered Metadynamics

Autoři

HALDAR, Susanta; Petra KUHROVÁ; Pavel BANÁŠ; Vojtěch SPIWOK; Jiří ŠPONER; Pavel HOBZA a Michal OTYEPKA

Vydání

Journal of Chemical Theory and Computation, WASHINGTON, AMER CHEMICAL SOC, 2015, 1549-9618

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10403 Physical chemistry

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 5.301

Organizační jednotka

Středoevropský technologický institut

DOI

https://doi.org/10.1021/acs.jctc.5b00010

UT WoS

000359500000034

Klíčová slova anglicky

FREE-ENERGY LANDSCAPE; DI-GMP RIBOSWITCH; RNA HAIRPINS; DISTINCTIVE FEATURES; ANGSTROM RESOLUTION; HAMMERHEAD RIBOZYME; BACTERIAL RIBOSOME; REPLICA-EXCHANGE; SIMULATIONS; KINETICS

Štítky

neMU

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 30. 3. 2016 16:56, Mgr. Eva Špillingová

Anotace

V originále

RNA hairpins capped by 5'-GNRA-3' or 5'-UNCG-3' tetraloops (TLs) are prominent RNA structural motifs. Despite their small size, a wealth of experimental data, and recent progress in theoretical simulations of their structural dynamics and folding, our understanding of the folding and unfolding processes of these small RNA elements is still limited. Theoretical description of the folding and unfolding processes requires robust sampling, which can be achieved by either an exhaustive time scale in standard molecular dynamics simulations or sophisticated enhanced sampling methods, using temperature acceleration or biasing potentials. Here, we study structural dynamics of 5'-GNRA-3' and 5'-UNCG-3' TLs by 15,us-long standard simulations and a series of well-tempered metadynamics, attempting to accelerate sampling by bias in a few chosen collective variables (CVs). Both methods provide useful insights. The unfolding and refolding mechanisms of the GNRA TL observed by well-tempered metadynamics agree with the (reverse) folding mechanism suggested by recent replica exchange molecular dynamics simulations. The orientation of the glycosidic bond of the G(L4) nudeobase is critical for the UUCG TL folding pathway, and our data strongly support the hypothesis that G(L4)-anti forms a kinetic trap along the folding pathway. Along with giving useful insight, our study also demonstrates that using only a few CVs apparently does not capture the full folding landscape of the RNA TLs. Despite using several sophisticated selections of the CVs, formation of the loop appears to remain a hidden variable, preventing a full convergence of the metadynamics. Finally, our data suggest that the unfolded state might be overstabilized by the force fields used.

Citovat

HALDAR, Susanta; Petra KUHROVÁ; Pavel BANÁŠ; Vojtěch SPIWOK; Jiří ŠPONER; Pavel HOBZA a Michal OTYEPKA. Insights into Stability and Folding of GNRA and UNCG Tetra loops Revealed by Microsecond Molecular Dynamics and Well-Tempered Metadynamics. Journal of Chemical Theory and Computation. WASHINGTON: AMER CHEMICAL SOC, 2015, roč. 11, č. 8, s. 3866-3877. ISSN 1549-9618. Dostupné z: https://doi.org/10.1021/acs.jctc.5b00010.

@article{1312043,
   author = {Haldar, Susanta and Kuhrová, Petra and Banáš, Pavel and Spiwok, Vojtěch and Šponer, Jiří and Hobza, Pavel and Otyepka, Michal},
   article_location = {WASHINGTON},
   article_number = {8},
   doi = {https://doi.org/10.1021/acs.jctc.5b00010},
   keywords = {FREE-ENERGY LANDSCAPE; DI-GMP RIBOSWITCH; RNA HAIRPINS; DISTINCTIVE FEATURES; ANGSTROM RESOLUTION; HAMMERHEAD RIBOZYME; BACTERIAL RIBOSOME; REPLICA-EXCHANGE; SIMULATIONS; KINETICS},
   language = {eng},
   issn = {1549-9618},
   journal = {Journal of Chemical Theory and Computation},
   title = {Insights into Stability and Folding of GNRA and UNCG Tetra loops Revealed by Microsecond Molecular Dynamics and Well-Tempered Metadynamics},
   url = {http://pubs.acs.org/doi/pdf/10.1021/acs.jctc.5b00010},
   volume = {11},
   year = {2015}
}

TY  - JOUR
ID  - 1312043
AU  - Haldar, Susanta - Kuhrová, Petra - Banáš, Pavel - Spiwok, Vojtěch - Šponer, Jiří - Hobza, Pavel - Otyepka, Michal
PY  - 2015
TI  - Insights into Stability and Folding of GNRA and UNCG Tetra loops Revealed by Microsecond Molecular Dynamics and Well-Tempered Metadynamics
JF  - Journal of Chemical Theory and Computation
VL  - 11
IS  - 8
SP  - 3866-3877
EP  - 3866-3877
PB  - AMER CHEMICAL SOC
SN  - 15499618
KW  - FREE-ENERGY LANDSCAPE
KW  - DI-GMP RIBOSWITCH
KW  - RNA HAIRPINS
KW  - DISTINCTIVE FEATURES
KW  - ANGSTROM RESOLUTION
KW  - HAMMERHEAD RIBOZYME
KW  - BACTERIAL RIBOSOME
KW  - REPLICA-EXCHANGE
KW  - SIMULATIONS
KW  - KINETICS
UR  - http://pubs.acs.org/doi/pdf/10.1021/acs.jctc.5b00010
L2  - http://pubs.acs.org/doi/pdf/10.1021/acs.jctc.5b00010
N2  - RNA hairpins capped by 5'-GNRA-3' or 5'-UNCG-3' tetraloops (TLs) are prominent RNA structural motifs. Despite their small size, a wealth of experimental data, and recent progress in theoretical simulations of their structural dynamics and folding, our understanding of the folding and unfolding processes of these small RNA elements is still limited. Theoretical description of the folding and unfolding processes requires robust sampling, which can be achieved by either an exhaustive time scale in standard molecular dynamics simulations or sophisticated enhanced sampling methods, using temperature acceleration or biasing potentials. Here, we study structural dynamics of 5'-GNRA-3' and 5'-UNCG-3' TLs by 15,us-long standard simulations and a series of well-tempered metadynamics, attempting to accelerate sampling by bias in a few chosen collective variables (CVs). Both methods provide useful insights. The unfolding and refolding mechanisms of the GNRA TL observed by well-tempered metadynamics agree with the (reverse) folding mechanism suggested by recent replica exchange molecular dynamics simulations. The orientation of the glycosidic bond of the G(L4) nudeobase is critical for the UUCG TL folding pathway, and our data strongly support the hypothesis that G(L4)-anti forms a kinetic trap along the folding pathway. Along with giving useful insight, our study also demonstrates that using only a few CVs apparently does not capture the full folding landscape of the RNA TLs. Despite using several sophisticated selections of the CVs, formation of the loop appears to remain a hidden variable, preventing a full convergence of the metadynamics. Finally, our data suggest that the unfolded state might be overstabilized by the force fields used.
ER  -

HALDAR, Susanta; Petra KUHROVÁ; Pavel BANÁŠ; Vojtěch SPIWOK; Jiří ŠPONER; Pavel HOBZA a Michal OTYEPKA. Insights into Stability and Folding of GNRA and UNCG Tetra loops Revealed by Microsecond Molecular Dynamics and Well-Tempered Metadynamics. \textit{Journal of Chemical Theory and Computation}. WASHINGTON: AMER CHEMICAL SOC, 2015, roč.~11, č.~8, s.~3866-3877. ISSN~1549-9618. Dostupné z: https://doi.org/10.1021/acs.jctc.5b00010.

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