Amyloid beta Fibril Elongation by Monomers Involves Disorder at the Tip

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F17%3A00481007" target="_blank" >RIV/61388963:_____/17:00481007 - isvavai.cz</a>

Výsledek na webu

<a href="http://dx.doi.org/10.1021/acs.jctc.7b00662" target="_blank" >http://dx.doi.org/10.1021/acs.jctc.7b00662</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jctc.7b00662" target="_blank" >10.1021/acs.jctc.7b00662</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Amyloid beta Fibril Elongation by Monomers Involves Disorder at the Tip

Popis výsledku v původním jazyce

The growth of amyloid fibrils from A beta(1-42) peptide, one of the key pathogenic players in Alzheimer's disease, is believed to follow a nucleation-elongation mechanism. Fibril elongation is often described as a ”dock-lock” procedure, where a disordered monomer adsorbs to an existing fibril in a relatively fast process (docking), followed by a slower conformational transition toward the ordered state of the template (locking). Here, we use molecular dynamics simulations of an ordered pentamer of A beta 42 at fully atomistic resolution, which includes solvent, to characterize the elongation process. We construct a Markov state model from an ensemble of short trajectories generated by an advanced sampling algorithm that efficiently diversifies a subset of the system without any bias forces. This subset corresponds to selected dihedral angles of the peptide chain at the fibril tip favored to be the fast growing one experimentally. From the network model, we extract distinct locking pathways covering time scales in the high microsecond regime. Slow steps are associated with the exchange of hydrophobic contacts, between nonnative and native intermolecular contacts as well as between intra- and intermolecular ones. The N-terminal segments, which are disordered in fibrils and typically considered inert, are able to shield the lateral interfaces of the pentamer. We conclude by discussing our findings in the context of a refined dock-lock model of A beta fibril elongation, which involves structural disorder for more than one monomer at the growing tip.

Název v anglickém jazyce

Amyloid beta Fibril Elongation by Monomers Involves Disorder at the Tip

Popis výsledku anglicky

The growth of amyloid fibrils from A beta(1-42) peptide, one of the key pathogenic players in Alzheimer's disease, is believed to follow a nucleation-elongation mechanism. Fibril elongation is often described as a ”dock-lock” procedure, where a disordered monomer adsorbs to an existing fibril in a relatively fast process (docking), followed by a slower conformational transition toward the ordered state of the template (locking). Here, we use molecular dynamics simulations of an ordered pentamer of A beta 42 at fully atomistic resolution, which includes solvent, to characterize the elongation process. We construct a Markov state model from an ensemble of short trajectories generated by an advanced sampling algorithm that efficiently diversifies a subset of the system without any bias forces. This subset corresponds to selected dihedral angles of the peptide chain at the fibril tip favored to be the fast growing one experimentally. From the network model, we extract distinct locking pathways covering time scales in the high microsecond regime. Slow steps are associated with the exchange of hydrophobic contacts, between nonnative and native intermolecular contacts as well as between intra- and intermolecular ones. The N-terminal segments, which are disordered in fibrils and typically considered inert, are able to shield the lateral interfaces of the pentamer. We conclude by discussing our findings in the context of a refined dock-lock model of A beta fibril elongation, which involves structural disorder for more than one monomer at the growing tip.

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

2017

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

13

Číslo periodika v rámci svazku

10

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

14

Strana od-do

5117-5130

Kód UT WoS článku

000412965700043

EID výsledku v databázi Scopus

2-s2.0-85032217719