AMBER and CHARMM Force Fields Inconsistently Portray the Microscopic Details of Phosphorylation

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F19%3A00501431" target="_blank" >RIV/61388963:_____/19:00501431 - isvavai.cz</a>

Výsledek na webu

<a href="https://pubs.acs.org/doi/10.1021/acs.jctc.8b00715" target="_blank" >https://pubs.acs.org/doi/10.1021/acs.jctc.8b00715</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jctc.8b00715" target="_blank" >10.1021/acs.jctc.8b00715</a>

Jazyk výsledku

angličtina

Název v původním jazyce

AMBER and CHARMM Force Fields Inconsistently Portray the Microscopic Details of Phosphorylation

Popis výsledku v původním jazyce

Phosphorylation of serine, threonine, and tyrosine is one of the most frequently occurring and crucial post-translational modifications of proteins often associated with important structural and functional changes. We investigated the direct effect of phosphorylation on the intrinsic conformational preferences of amino acids as a potential trigger of larger structural events. We conducted a comparative study of force fields on terminally capped amino acids (dipeptides) as the simplest model for phosphorylation. Our bias-exchange metadynamics simulations revealed that all model dipeptides sampled a great heterogeneity of ensembles affected by introduction of mono- and dianionic phosphate groups. However, the detected changes in populations of backbone conformers and side-chain rotamers did not reveal a strong discriminatory shift in preferences, as could be anticipated for the bulky, charged phosphate group. Furthermore, the AMBER and CHARMM force fields provided inconsistent populations of individual conformers as well as net structural trends upon phosphorylation. Detailed analysis of ensembles revealed competition between hydration and formation of internal hydrogen bonds involving amide hydrogens and the phosphate group. The observed difference in hydration free energy and potential for hydrogen bonding in individual force fields could be attributed to the different partial atomic charges used in each force field and, hence, the different parametrization strategies. Nevertheless, conformational propensities and net structural changes upon phosphorylation are difficult to extract from experimental measurements, and existing experimental data provide limited guidance for force field assessment and further development.

Název v anglickém jazyce

AMBER and CHARMM Force Fields Inconsistently Portray the Microscopic Details of Phosphorylation

Popis výsledku anglicky

Phosphorylation of serine, threonine, and tyrosine is one of the most frequently occurring and crucial post-translational modifications of proteins often associated with important structural and functional changes. We investigated the direct effect of phosphorylation on the intrinsic conformational preferences of amino acids as a potential trigger of larger structural events. We conducted a comparative study of force fields on terminally capped amino acids (dipeptides) as the simplest model for phosphorylation. Our bias-exchange metadynamics simulations revealed that all model dipeptides sampled a great heterogeneity of ensembles affected by introduction of mono- and dianionic phosphate groups. However, the detected changes in populations of backbone conformers and side-chain rotamers did not reveal a strong discriminatory shift in preferences, as could be anticipated for the bulky, charged phosphate group. Furthermore, the AMBER and CHARMM force fields provided inconsistent populations of individual conformers as well as net structural trends upon phosphorylation. Detailed analysis of ensembles revealed competition between hydration and formation of internal hydrogen bonds involving amide hydrogens and the phosphate group. The observed difference in hydration free energy and potential for hydrogen bonding in individual force fields could be attributed to the different partial atomic charges used in each force field and, hence, the different parametrization strategies. Nevertheless, conformational propensities and net structural changes upon phosphorylation are difficult to extract from experimental measurements, and existing experimental data provide limited guidance for force field assessment and further development.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10403 - Physical chemistry

Projekt

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

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2019

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

15

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

15

Strana od-do

665-679

Kód UT WoS článku

000455558200058

EID výsledku v databázi Scopus

2-s2.0-85058544605