Multiscale Simulation of Phosphofructokinase-1 Assemblies: Capturing the Interplay between Specific and Transient Interactions

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388955%3A_____%2F25%3A00642022" target="_blank" >RIV/61388955:_____/25:00642022 - isvavai.cz</a>

Výsledek na webu

<a href="https://pubs.acs.org/doi/full/10.1021/acs.jpcb.5c05346" target="_blank" >https://pubs.acs.org/doi/full/10.1021/acs.jpcb.5c05346</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jpcb.5c05346" target="_blank" >10.1021/acs.jpcb.5c05346</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Multiscale Simulation of Phosphofructokinase-1 Assemblies: Capturing the Interplay between Specific and Transient Interactions

Popis výsledku v původním jazyce

Human phosphofructokinase-1 (PFK1) forms filaments and organizes into large-scale assemblies that are thought to play a key role in the spatial organization of glycolysis. However, the molecular interactions driving this assembly and the isoform-specific tendencies to form such structures remain poorly understood. In this work, we combine coarse-grained and all-atom molecular dynamics simulations to characterize interactions between PFK1 tetramers. Using the Martini and OPEPv7 coarse-grained force fields, we identify key regions mediating transient PFK1–PFK1 interactions and show that these include experimentally identified filament-forming interfaces. At the same time, we find that current coarse-grained models─optimized for nonspecific, transient contacts─lack the resolution to capture the specific side-chain interactions critical for filament stability, as revealed by previous experiments and our all-atom simulations. To address this, we propose enhancing the coarse-grained representation of filament-forming interfaces by introducing additional hydrogen-bonding terms for key residues. This modification improves filament stability and more accurately reproduces the effects of the filament-disrupting Asn-to-Thr mutation. Overall, our work provides a foundation for molecular-level modeling of glycolytic enzyme assemblies and offers a strategy to improve the accuracy of coarse-grained models in capturing the delicate interplay between specific and transient interactions in dynamic protein complexes.

Název v anglickém jazyce

Multiscale Simulation of Phosphofructokinase-1 Assemblies: Capturing the Interplay between Specific and Transient Interactions

Popis výsledku anglicky

Human phosphofructokinase-1 (PFK1) forms filaments and organizes into large-scale assemblies that are thought to play a key role in the spatial organization of glycolysis. However, the molecular interactions driving this assembly and the isoform-specific tendencies to form such structures remain poorly understood. In this work, we combine coarse-grained and all-atom molecular dynamics simulations to characterize interactions between PFK1 tetramers. Using the Martini and OPEPv7 coarse-grained force fields, we identify key regions mediating transient PFK1–PFK1 interactions and show that these include experimentally identified filament-forming interfaces. At the same time, we find that current coarse-grained models─optimized for nonspecific, transient contacts─lack the resolution to capture the specific side-chain interactions critical for filament stability, as revealed by previous experiments and our all-atom simulations. To address this, we propose enhancing the coarse-grained representation of filament-forming interfaces by introducing additional hydrogen-bonding terms for key residues. This modification improves filament stability and more accurately reproduces the effects of the filament-disrupting Asn-to-Thr mutation. Overall, our work provides a foundation for molecular-level modeling of glycolytic enzyme assemblies and offers a strategy to improve the accuracy of coarse-grained models in capturing the delicate interplay between specific and transient interactions in dynamic protein complexes.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10403 - Physical chemistry

Projekt

<a href="/cs/project/GA23-06437S" target="_blank" >GA23-06437S: Alosterie a prostorová organizace v glykolýze: úloha fosfofruktokinázy 1</a><br>

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 Physical Chemistry C

ISSN

1932-7447

e-ISSN

1932-7455

Svazek periodika

129

Číslo periodika v rámci svazku

47

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

12

Strana od-do

12098-12109

Kód UT WoS článku

001616529200001

EID výsledku v databázi Scopus

2-s2.0-105023177341