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

Result code in 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>

Alternative codes found

RIV/61989592:15310/16:33161434

Result on the web

<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>

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

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Czech description

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Type

J_x - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)

CEP classification

BO - Biophysics

OECD FORD branch

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Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2016

Confidentiality

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

Name of the periodical

Journal of Chemical Theory and Computation

ISSN

1549-9618

e-ISSN

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Volume of the periodical

12

Issue of the periodical within the volume

9

Country of publishing house

US - UNITED STATES

Number of pages

15

Pages from-to

4534-4548

UT code for WoS article

000383315700033

EID of the result in the Scopus database

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