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@article{2248161,
author = {Pokorná, Pavlína and Krepl, Miroslav and Campagne, Sébastien and Šponer, Jiří},
article_number = {45},
doi = {http://dx.doi.org/10.1021/acs.jpcb.2c06168},
keywords = {Chemical structure; Computational chemistry; Conformation; Genetics; Molecular mechanics},
language = {eng},
issn = {1520-6106},
journal = {Journal of Physical Chemistry B},
title = {Conformational Heterogeneity of RNA Stem-Loop Hairpins Bound to FUS-RNA Recognition Motif with Disordered RGG Tail Revealed by Unbiased Molecular Dynamics Simulations},
url = {https://doi.org/10.1021/acs.jpcb.2c06168},
volume = {126},
year = {2022}
}
TY - JOUR
ID - 2248161
AU - Pokorná, Pavlína - Krepl, Miroslav - Campagne, Sébastien - Šponer, Jiří
PY - 2022
TI - Conformational Heterogeneity of RNA Stem-Loop Hairpins Bound to FUS-RNA Recognition Motif with Disordered RGG Tail Revealed by Unbiased Molecular Dynamics Simulations
JF - Journal of Physical Chemistry B
VL - 126
IS - 45
SP - 9207-9221
EP - 9207-9221
PB - American Chemical Society
SN - 15206106
KW - Chemical structure
KW - Computational chemistry
KW - Conformation
KW - Genetics
KW - Molecular mechanics
UR - https://doi.org/10.1021/acs.jpcb.2c06168
N2 - RNA–protein complexes use diverse binding strategies, ranging from structurally well-defined interfaces to completely disordered regions. Experimental characterization of flexible segments is challenging and can be aided by atomistic molecular dynamics (MD) simulations. Here, we used an extended set of microsecond-scale MD trajectories (400 μs in total) to study two FUS-RNA constructs previously characterized by nuclear magnetic resonance (NMR) spectroscopy. The FUS protein contains a well-structured RNA recognition motif domain followed by a presumably disordered RGG tail that binds RNA stem-loop hairpins. Our simulations not only provide several suggestions complementing the experiments but also reveal major methodological difficulties in studies of such complex RNA–protein interfaces. Despite efforts to stabilize the binding via system-specific force-field adjustments, we have observed progressive distortions of the RNA–protein interface inconsistent with experimental data. We propose that the dynamics is so rich that its converged description is not achievable even upon stabilizing the system. Still, after careful analysis of the trajectories, we have made several suggestions regarding the binding. We identify substates in the RNA loops, which can explain the NMR data. The RGG tail localized in the minor groove remains disordered, sampling countless transient interactions with the RNA. There are long-range couplings among the different elements contributing to the recognition, which can lead to allosteric communication throughout the system. Overall, the RNA-FUS systems form dynamical ensembles that cannot be fully represented by single static structures. Thus, albeit imperfect, MD simulations represent a viable tool to investigate dynamic RNA–protein complexes.
ER -
POKORNÁ, Pavlína, Miroslav KREPL, Sébastien CAMPAGNE a Jiří ŠPONER. Conformational Heterogeneity of RNA Stem-Loop Hairpins Bound to FUS-RNA Recognition Motif with Disordered RGG Tail Revealed by Unbiased Molecular Dynamics Simulations. \textit{Journal of Physical Chemistry B}. American Chemical Society, 2022, roč.~126, č.~45, s.~9207-9221. ISSN~1520-6106. Dostupné z: https://dx.doi.org/10.1021/acs.jpcb.2c06168.
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