Evolution of large Aβ16–22 aggregates at atomic details and potential of mean force associated to peptide unbinding and fragmentation events

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388955%3A_____%2F23%3A00571825" target="_blank" >RIV/61388955:_____/23:00571825 - isvavai.cz</a>

Výsledek na webu

<a href="https://hdl.handle.net/11104/0342729" target="_blank" >https://hdl.handle.net/11104/0342729</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/prot.26500" target="_blank" >10.1002/prot.26500</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Evolution of large Aβ16–22 aggregates at atomic details and potential of mean force associated to peptide unbinding and fragmentation events

Popis výsledku v původním jazyce

Atomic characterization of large nonfibrillar aggregates of amyloid polypeptides cannot be determined by experimental means. Starting from β-rich aggregates of Y and elongated topologies predicted by coarse-grained simulations and consisting of more than 100 Aβ16–22 peptides, we performed atomistic molecular dynamics (MD), replica exchange with solute scaling (REST2), and umbrella sampling simulations using the CHARMM36m force field in explicit solvent. Here, we explored the dynamics within 3 μs, the free energy landscape, and the potential of mean force associated with either the unbinding of one single peptide in different configurations within the aggregate or fragmentation events of a large number of peptides. Within the time scale of MD and REST2, we find that the aggregates experience slow global conformational plasticity, and remain essentially random coil though we observe slow beta-strand structuring with a dominance of antiparallel beta-sheets over parallel beta-sheets. Enhanced REST2 simulation is able to capture fragmentation events, and the free energy of fragmentation of a large block of peptides is found to be similar to the free energy associated with fibril depolymerization by one chain for longer Aβ sequences.n

Název v anglickém jazyce

Evolution of large Aβ16–22 aggregates at atomic details and potential of mean force associated to peptide unbinding and fragmentation events

Popis výsledku anglicky

Atomic characterization of large nonfibrillar aggregates of amyloid polypeptides cannot be determined by experimental means. Starting from β-rich aggregates of Y and elongated topologies predicted by coarse-grained simulations and consisting of more than 100 Aβ16–22 peptides, we performed atomistic molecular dynamics (MD), replica exchange with solute scaling (REST2), and umbrella sampling simulations using the CHARMM36m force field in explicit solvent. Here, we explored the dynamics within 3 μs, the free energy landscape, and the potential of mean force associated with either the unbinding of one single peptide in different configurations within the aggregate or fragmentation events of a large number of peptides. Within the time scale of MD and REST2, we find that the aggregates experience slow global conformational plasticity, and remain essentially random coil though we observe slow beta-strand structuring with a dominance of antiparallel beta-sheets over parallel beta-sheets. Enhanced REST2 simulation is able to capture fragmentation events, and the free energy of fragmentation of a large block of peptides is found to be similar to the free energy associated with fibril depolymerization by one chain for longer Aβ sequences.n

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10403 - Physical chemistry

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2023

Kód důvěrnosti údajů

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

Název periodika

Proteins-Structure, Function and Bioinformatics

ISSN

0887-3585

e-ISSN

1097-0134

Svazek periodika

91

Číslo periodika v rámci svazku

8

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

11

Strana od-do

1152-1162

Kód UT WoS článku

000980796300001

EID výsledku v databázi Scopus

2-s2.0-85158134316