How Binding Site Flexibility Promotes RNA Scanning by TbRGG2
RRM: A Molecular Dynamics Simulation Study

J 2025

How Binding Site Flexibility Promotes RNA Scanning by TbRGG2 RRM: A Molecular Dynamics Simulation Study

LEMMENS, Toon; Jiří ŠPONER and Miroslav KREPL

Basic information

Original name

How Binding Site Flexibility Promotes RNA Scanning by TbRGG2 RRM: A Molecular Dynamics Simulation Study

Authors

LEMMENS, Toon (56 Belgium, belonging to the institution); Jiří ŠPONER (203 Czech Republic) and Miroslav KREPL (203 Czech Republic, guarantor)

Edition

Journal of Chemical Information and Modeling, American Chemical Society, 2025, 1549-9596

Other information

Language

English

Type of outcome

Article in a journal

Field of Study

10610 Biophysics

Country of publisher

United States of America

Confidentiality degree

is not subject to a state or trade secret

References:

URL

Impact factor

Impact factor: 5.700 in 2023

Organization unit

Faculty of Science

DOI

http://dx.doi.org/10.1021/acs.jcim.4c01954

UT WoS

001396998800001

EID Scopus

2-s2.0-85215846781

Keywords in English

RRM; Molecular Dynamics; TbRGG2; kRNA editing; Stafix

Abstract

In the original language

RNA recognition motifs (RRMs) are a key class of proteins that primarily bind single-stranded RNAs. In this study, we applied standard atomistic molecular dynamics simulations to obtain insights into the intricate binding dynamics between uridine-rich RNAs and TbRGG2 RRM using the recently developed OL3-Stafix AMBER force field, which improves the description of single-stranded RNA molecules. Complementing structural experiments that unveil a primary binding mode with a single uridine bound, our simulations uncover two supplementary binding modes in which adjacent nucleotides encroach upon the binding pocket. This leads to a unique molecular mechanism through which the TbRGG2 RRM is capable of rapidly transitioning the U-rich sequence. In contrast, the presence of non-native cytidines induces stalling and destabilization of the complex. By leveraging extensive equilibrium dynamics and a large variety of binding states, TbRGG2 RRM effectively expedites diffusion along the RNA substrate while ensuring robust selectivity for U-rich sequences despite featuring a solitary binding pocket. We further substantiate our description of the complex dynamics by simulating the fully spontaneous association process of U-rich sequences to the TbRGG2 RRM. Our study highlights the critical role of dynamics and auxiliary binding states in interface dynamics employed by RNA-binding proteins, which is not readily apparent in traditional structural studies but could represent a general type of binding strategy employed by many RNA-binding proteins.

Cite

LEMMENS, Toon; Jiří ŠPONER and Miroslav KREPL. How Binding Site Flexibility Promotes RNA Scanning by TbRGG2 RRM: A Molecular Dynamics Simulation Study. Journal of Chemical Information and Modeling. American Chemical Society, 2025, vol. 65, No 2, p. 896-907. ISSN 1549-9596. Available from: https://dx.doi.org/10.1021/acs.jcim.4c01954.

@article{2469717,
   author = {Lemmens, Toon and Šponer, Jiří and Krepl, Miroslav},
   article_number = {2},
   doi = {http://dx.doi.org/10.1021/acs.jcim.4c01954},
   keywords = {RRM; Molecular Dynamics; TbRGG2; kRNA editing; Stafix},
   language = {eng},
   issn = {1549-9596},
   journal = {Journal of Chemical Information and Modeling},
   title = {How Binding Site Flexibility Promotes RNA Scanning by TbRGG2 RRM: A Molecular Dynamics Simulation Study},
   url = {https://pubs.acs.org/doi/full/10.1021/acs.jcim.4c01954},
   volume = {65},
   year = {2025}
}

TY  - JOUR
ID  - 2469717
AU  - Lemmens, Toon - Šponer, Jiří - Krepl, Miroslav
PY  - 2025
TI  - How Binding Site Flexibility Promotes RNA Scanning by TbRGG2 RRM: A Molecular Dynamics Simulation Study
JF  - Journal of Chemical Information and Modeling
VL  - 65
IS  - 2
SP  - 896-907
EP  - 896-907
PB  - American Chemical Society
SN  - 15499596
KW  - RRM
KW  - Molecular Dynamics
KW  - TbRGG2
KW  - kRNA editing
KW  - Stafix
UR  - https://pubs.acs.org/doi/full/10.1021/acs.jcim.4c01954
N2  - RNA recognition motifs (RRMs) are a key class of proteins that primarily bind single-stranded RNAs. In this study, we applied standard atomistic molecular dynamics simulations to obtain insights into the intricate binding dynamics between uridine-rich RNAs and TbRGG2 RRM using the recently developed OL3-Stafix AMBER force field, which improves the description of single-stranded RNA molecules. Complementing structural experiments that unveil a primary binding mode with a single uridine bound, our simulations uncover two supplementary binding modes in which adjacent nucleotides encroach upon the binding pocket. This leads to a unique molecular mechanism through which the TbRGG2 RRM is capable of rapidly transitioning the U-rich sequence. In contrast, the presence of non-native cytidines induces stalling and destabilization of the complex. By leveraging extensive equilibrium dynamics and a large variety of binding states, TbRGG2 RRM effectively expedites diffusion along the RNA substrate while ensuring robust selectivity for U-rich sequences despite featuring a solitary binding pocket. We further substantiate our description of the complex dynamics by simulating the fully spontaneous association process of U-rich sequences to the TbRGG2 RRM. Our study highlights the critical role of dynamics and auxiliary binding states in interface dynamics employed by RNA-binding proteins, which is not readily apparent in traditional structural studies but could represent a general type of binding strategy employed by many RNA-binding proteins.
ER  -

LEMMENS, Toon; Jiří ŠPONER and Miroslav KREPL. How Binding Site Flexibility Promotes RNA Scanning by TbRGG2 RRM: A Molecular Dynamics Simulation Study. \textit{Journal of Chemical Information and Modeling}. American Chemical Society, 2025, vol.~65, No~2, p.~896-907. ISSN~1549-9596. Available from: https://dx.doi.org/10.1021/acs.jcim.4c01954.

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