Computer Folding of RNA Tetraloops: Identification of Key Force Field Deficiencies

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F16%3A00471959" target="_blank" >RIV/68081707:_____/16:00471959 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61989592:15310/16:33161434

Výsledek na webu

<a href="http://dx.doi.org/10.1021/acs.jctc.6b00300" target="_blank" >http://dx.doi.org/10.1021/acs.jctc.6b00300</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jctc.6b00300" target="_blank" >10.1021/acs.jctc.6b00300</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Computer Folding of RNA Tetraloops: Identification of Key Force Field Deficiencies

Popis výsledku v původním jazyce

The computer-aided folding of biomolecules, particularly RNAs, is one of the most difficult challenges in computational structural biology. RNA tetraloops are fundamental RNA motifs playing key roles in RNA folding and RNA RNA and RNA protein interactions. Although state-of-the-art Molecular Dynamics (MD) force fields correctly describe the native state of these tetraloops as a stable free-energy basin on the microsecond time scale,. enhanced sampling techniques reveal that the native state is not the global free energy minimum, suggesting yet unidentified significant imbalances in the force fields. Here, we tested our ability to fold the RNA tetraloops in various force fields and simulation settings. We employed three different enhanced sampling techniques, namely, temperature replica exchange MD (T-REMD), replica exchange with solute tempering (REST2), and well-tempered metadynamics (WT-MetaD). We aimed to separate problems caused by limited sampling from those due to force-field inaccuracies. We found that none of the contemporary force fields is able to correctly describe folding of the 5'-GAGA-3' tetraloop over a range of simulation conditions. We thus aimed to identify which terms of the force field are responsible for this poor description of TL folding. We showed that at least two different imbalances contribute to this behavior, namely, overstabilization of base phosphate and/or sugar phosphate interactions and underestimated stability of the hydrogen bonding interaction in base pairing. The first artifact stabilizes the unfolded ensemble, while the second one destabilizes the folded state. The former problem might be partially alleviated by reparametrization of the van der Waals parameters of the phosphate oxygens suggested by Case et al., while in order to overcome the latter effect we suggest local potentials to better capture hydrogen bonding interactions.

Název v anglickém jazyce

Computer Folding of RNA Tetraloops: Identification of Key Force Field Deficiencies

Popis výsledku anglicky

The computer-aided folding of biomolecules, particularly RNAs, is one of the most difficult challenges in computational structural biology. RNA tetraloops are fundamental RNA motifs playing key roles in RNA folding and RNA RNA and RNA protein interactions. Although state-of-the-art Molecular Dynamics (MD) force fields correctly describe the native state of these tetraloops as a stable free-energy basin on the microsecond time scale,. enhanced sampling techniques reveal that the native state is not the global free energy minimum, suggesting yet unidentified significant imbalances in the force fields. Here, we tested our ability to fold the RNA tetraloops in various force fields and simulation settings. We employed three different enhanced sampling techniques, namely, temperature replica exchange MD (T-REMD), replica exchange with solute tempering (REST2), and well-tempered metadynamics (WT-MetaD). We aimed to separate problems caused by limited sampling from those due to force-field inaccuracies. We found that none of the contemporary force fields is able to correctly describe folding of the 5'-GAGA-3' tetraloop over a range of simulation conditions. We thus aimed to identify which terms of the force field are responsible for this poor description of TL folding. We showed that at least two different imbalances contribute to this behavior, namely, overstabilization of base phosphate and/or sugar phosphate interactions and underestimated stability of the hydrogen bonding interaction in base pairing. The first artifact stabilizes the unfolded ensemble, while the second one destabilizes the folded state. The former problem might be partially alleviated by reparametrization of the van der Waals parameters of the phosphate oxygens suggested by Case et al., while in order to overcome the latter effect we suggest local potentials to better capture hydrogen bonding interactions.

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

BO - Biofyzika

OECD FORD obor

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Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2016

Kód důvěrnosti údajů

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

Název periodika

Journal of Chemical Theory and Computation

ISSN

1549-9618

e-ISSN

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Svazek periodika

12

Číslo periodika v rámci svazku

9

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

15

Strana od-do

4534-4548

Kód UT WoS článku

000383315700033

EID výsledku v databázi Scopus

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