Molecular Simulations to Investigate the Impact of N6-Methylation in RNA Recognition: Improving Accuracy and Precision of Binding Free Energy Prediction

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F24%3A00598549" target="_blank" >RIV/68081707:_____/24:00598549 - isvavai.cz</a>

Výsledek na webu

<a href="https://pubs.acs.org/doi/10.1021/acs.jpcb.4c03397" target="_blank" >https://pubs.acs.org/doi/10.1021/acs.jpcb.4c03397</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jpcb.4c03397" target="_blank" >10.1021/acs.jpcb.4c03397</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Molecular Simulations to Investigate the Impact of N6-Methylation in RNA Recognition: Improving Accuracy and Precision of Binding Free Energy Prediction

Popis výsledku v původním jazyce

N6-Methyladenosine (m(6)A) is a prevalent RNA post-transcriptional modification that plays crucial roles in RNA stability, structural dynamics, and interactions with proteins. The YT521-B (YTH) family of proteins, which are notable m6A readers, functions through its highly conserved YTH domain. Recent structural investigations and molecular dynamics (MD) simulations have shed light on the mechanism of recognition of m(6)A by the YTHDC1 protein. Despite advancements, using MD to predict the stabilization induced by m(6)A on the free energy of binding between RNA and YTH proteins remains challenging due to inaccuracy of the employed force field and limited sampling. For instance, simulations often fail to sufficiently capture the hydration dynamics of the binding pocket. This study addresses these challenges through an innovative methodology that integrates metadynamics, alchemical simulations, and force-field refinement. Importantly, our research identifies hydration of the binding pocket as giving only a minor contribution to the binding free energy and emphasizes the critical importance of precisely tuning force-field parameters to experimental data. By employing a fitting strategy built on alchemical calculations, we refine the m(6)A partial charge parameters, thereby enabling the simultaneous reproduction of N6 methylation on both the protein binding free energy and the thermodynamic stability of nine RNA duplexes. Our findings underscore the sensitivity of binding free energies to partial charges, highlighting the necessity for thorough parametrization and validation against experimental observations across a range of structural contexts.

Název v anglickém jazyce

Molecular Simulations to Investigate the Impact of N6-Methylation in RNA Recognition: Improving Accuracy and Precision of Binding Free Energy Prediction

Popis výsledku anglicky

N6-Methyladenosine (m(6)A) is a prevalent RNA post-transcriptional modification that plays crucial roles in RNA stability, structural dynamics, and interactions with proteins. The YT521-B (YTH) family of proteins, which are notable m6A readers, functions through its highly conserved YTH domain. Recent structural investigations and molecular dynamics (MD) simulations have shed light on the mechanism of recognition of m(6)A by the YTHDC1 protein. Despite advancements, using MD to predict the stabilization induced by m(6)A on the free energy of binding between RNA and YTH proteins remains challenging due to inaccuracy of the employed force field and limited sampling. For instance, simulations often fail to sufficiently capture the hydration dynamics of the binding pocket. This study addresses these challenges through an innovative methodology that integrates metadynamics, alchemical simulations, and force-field refinement. Importantly, our research identifies hydration of the binding pocket as giving only a minor contribution to the binding free energy and emphasizes the critical importance of precisely tuning force-field parameters to experimental data. By employing a fitting strategy built on alchemical calculations, we refine the m(6)A partial charge parameters, thereby enabling the simultaneous reproduction of N6 methylation on both the protein binding free energy and the thermodynamic stability of nine RNA duplexes. Our findings underscore the sensitivity of binding free energies to partial charges, highlighting the necessity for thorough parametrization and validation against experimental observations across a range of structural contexts.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10403 - Physical chemistry

Projekt

<a href="/cs/project/GA23-05639S" target="_blank" >GA23-05639S: Molekulové simulace RNA: od statických struktur k molekulárním souborům</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2024

Kód důvěrnosti údajů

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

Název periodika

Journal of Physical Chemistry B

ISSN

1520-6106

e-ISSN

1520-5207

Svazek periodika

128

Číslo periodika v rámci svazku

37

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

12

Strana od-do

8896-8907

Kód UT WoS článku

001308702100001

EID výsledku v databázi Scopus

2-s2.0-85203415935