Can We Ever Develop an Ideal RNA Force Field? Lessons Learned from Simulations of the UUCG RNA Tetraloop and Other Systems

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F25%3A00644608" target="_blank" >RIV/68081707:_____/25:00644608 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61989592:15640/25:73630702 RIV/61989100:27740/25:10257473

Výsledek na webu

<a href="https://pubs.acs.org/doi/10.1021/acs.jctc.4c01357" target="_blank" >https://pubs.acs.org/doi/10.1021/acs.jctc.4c01357</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jctc.4c01357" target="_blank" >10.1021/acs.jctc.4c01357</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Can We Ever Develop an Ideal RNA Force Field? Lessons Learned from Simulations of the UUCG RNA Tetraloop and Other Systems

Popis výsledku v původním jazyce

Molecular dynamics (MD) simulations are an important and well-established tool for investigating RNA structural dynamics, but their accuracy relies heavily on the quality of the employed force field (ff). In this work, we present a comprehensive evaluation of widely used pair-additive and polarizable RNA ffs using the challenging UUCG tetraloop (TL) benchmark system. Extensive standard MD simulations, initiated from the NMR structure of the 14-mer UUCG TL, revealed that most ffs did not maintain the native state, instead favoring alternative loop conformations. Notably, three very recent variants of pair-additive ffs, OL3CP-gHBfix21, DES-Amber, and OL3R2.7, successfully preserved the native structure over a 10 x 20 mu s time scale. To further assess these ffs, we performed enhanced sampling folding simulations of the shorter 8-mer UUCG TL, starting from the single-stranded conformation. Estimated folding free energies (Delta G degrees fold) varied significantly among these three ffs, with values of 0.0 +/- 0.6, 2.4 +/- 0.8, and 7.4 +/- 0.2 kcal/mol for OL3CP-gHBfix21, DES-Amber, and OL3R2.7, respectively. The Delta G degrees fold value predicted by the OL3CP-gHBfix21 ff was closest to experimental estimates, ranging from1.6 to0.7 kcal/mol. In contrast, the higher Delta G degrees fold values obtained using DES-Amber and OL3R2.7 were unexpected, suggesting that key interactions are inaccurately described in the folded, unfolded, or misfolded ensembles. These discrepancies led us to further test DES-Amber and OL3R2.7 ffs on additional RNA and DNA systems, where further performance issues were observed. Our results emphasize the complexity of accurately modeling RNA dynamics and suggest that creating an RNA ff capable of reliably performing across a wide range of RNA systems remains extremely challenging. In conclusion, our study provides valuable insights into the capabilities of current RNA ffs and highlights key areas for future ff development.

Název v anglickém jazyce

Can We Ever Develop an Ideal RNA Force Field? Lessons Learned from Simulations of the UUCG RNA Tetraloop and Other Systems

Popis výsledku anglicky

Molecular dynamics (MD) simulations are an important and well-established tool for investigating RNA structural dynamics, but their accuracy relies heavily on the quality of the employed force field (ff). In this work, we present a comprehensive evaluation of widely used pair-additive and polarizable RNA ffs using the challenging UUCG tetraloop (TL) benchmark system. Extensive standard MD simulations, initiated from the NMR structure of the 14-mer UUCG TL, revealed that most ffs did not maintain the native state, instead favoring alternative loop conformations. Notably, three very recent variants of pair-additive ffs, OL3CP-gHBfix21, DES-Amber, and OL3R2.7, successfully preserved the native structure over a 10 x 20 mu s time scale. To further assess these ffs, we performed enhanced sampling folding simulations of the shorter 8-mer UUCG TL, starting from the single-stranded conformation. Estimated folding free energies (Delta G degrees fold) varied significantly among these three ffs, with values of 0.0 +/- 0.6, 2.4 +/- 0.8, and 7.4 +/- 0.2 kcal/mol for OL3CP-gHBfix21, DES-Amber, and OL3R2.7, respectively. The Delta G degrees fold value predicted by the OL3CP-gHBfix21 ff was closest to experimental estimates, ranging from1.6 to0.7 kcal/mol. In contrast, the higher Delta G degrees fold values obtained using DES-Amber and OL3R2.7 were unexpected, suggesting that key interactions are inaccurately described in the folded, unfolded, or misfolded ensembles. These discrepancies led us to further test DES-Amber and OL3R2.7 ffs on additional RNA and DNA systems, where further performance issues were observed. Our results emphasize the complexity of accurately modeling RNA dynamics and suggest that creating an RNA ff capable of reliably performing across a wide range of RNA systems remains extremely challenging. In conclusion, our study provides valuable insights into the capabilities of current RNA ffs and highlights key areas for future ff development.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

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

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

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

1549-9626

Svazek periodika

21

Číslo periodika v rámci svazku

8

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

20

Strana od-do

4183-4202

Kód UT WoS článku

001396622000001

EID výsledku v databázi Scopus

2-s2.0-105003177523