UUCG RNA Tetraloop as a Formidable Force-Field Challenge for MD Simulations

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F20%3A00540054" target="_blank" >RIV/68081707:_____/20:00540054 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61989592:15310/20:73604594 RIV/00216224:14310/20:00117388

Výsledek na webu

<a href="https://pubs.acs.org/doi/10.1021/acs.jctc.0c00801" target="_blank" >https://pubs.acs.org/doi/10.1021/acs.jctc.0c00801</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jctc.0c00801" target="_blank" >10.1021/acs.jctc.0c00801</a>

Jazyk výsledku

angličtina

Název v původním jazyce

UUCG RNA Tetraloop as a Formidable Force-Field Challenge for MD Simulations

Popis výsledku v původním jazyce

Explicit solvent atomistic molecular dynamics (MD) simulations represent an established technique to study structural dynamics of RNA molecules and an important complement for diverse experimental methods. However, performance of molecular mechanical (MM) force fields (Ifs) remains far from satisfactory even after decades of development, as apparent from a problematic structural description of some important RNA motifs. Actually, some of the smallest RNA molecules belong to the most challenging systems for MD simulations and, among them, the UUCG tetraloop is saliently difficult. We report a detailed analysis of UUCG MD ' simulations, depicting the sequence of events leading to the loss of 3finish the UUCG native state during MD simulations. The total amount of MD simulation data analyzed in this work is close to 1.3 ms. We identify molecular interactions, backbone conformations, and substates that are involved in the process. Then, we unravel specific ff deficiencies using diverse quantum mechanical/molecular mechanical (QM/MM) and QM calculations. Comparison between the MM and QM methods shows discrepancies in the description of the 5'-flanking phosphate moiety and both signature sugar-base interactions. Our work indicates that poor behavior of the UUCG tetraloop in simulations is a complex issue that cannot be attributed to one dominant and straightforwardly correctable factor. Instead, there is a concerted effect of multiple ff inaccuracies that are coupled and amplifying each other. We attempted to improve the simulation behavior by some carefully tailored interventions, but the results were still far from satisfactory, underlying the difficulties in development of accurate nucleic acid Ifs.

Název v anglickém jazyce

UUCG RNA Tetraloop as a Formidable Force-Field Challenge for MD Simulations

Popis výsledku anglicky

Explicit solvent atomistic molecular dynamics (MD) simulations represent an established technique to study structural dynamics of RNA molecules and an important complement for diverse experimental methods. However, performance of molecular mechanical (MM) force fields (Ifs) remains far from satisfactory even after decades of development, as apparent from a problematic structural description of some important RNA motifs. Actually, some of the smallest RNA molecules belong to the most challenging systems for MD simulations and, among them, the UUCG tetraloop is saliently difficult. We report a detailed analysis of UUCG MD ' simulations, depicting the sequence of events leading to the loss of 3finish the UUCG native state during MD simulations. The total amount of MD simulation data analyzed in this work is close to 1.3 ms. We identify molecular interactions, backbone conformations, and substates that are involved in the process. Then, we unravel specific ff deficiencies using diverse quantum mechanical/molecular mechanical (QM/MM) and QM calculations. Comparison between the MM and QM methods shows discrepancies in the description of the 5'-flanking phosphate moiety and both signature sugar-base interactions. Our work indicates that poor behavior of the UUCG tetraloop in simulations is a complex issue that cannot be attributed to one dominant and straightforwardly correctable factor. Instead, there is a concerted effect of multiple ff inaccuracies that are coupled and amplifying each other. We attempted to improve the simulation behavior by some carefully tailored interventions, but the results were still far from satisfactory, underlying the difficulties in development of accurate nucleic acid Ifs.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10301 - Atomic, molecular and chemical physics (physics of atoms and molecules including collision, interaction with radiation, magnetic resonances, Mössbauer effect)

Projekt

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

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2020

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

—

Svazek periodika

16

Číslo periodika v rámci svazku

12

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

17

Strana od-do

7601-7617

Kód UT WoS článku

000598208600027

EID výsledku v databázi Scopus

2-s2.0-85097584157