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@ARTICLE{Barz:150966,
author = {Barz, Bogdan and Wales, David J. and Strodel, Birgit},
title = {{A} {K}inetic {A}pproach to the {S}equence–{A}ggregation
{R}elationship in {D}isease-related {P}rotein {A}ssembly},
journal = {The journal of physical chemistry / B},
volume = {118},
number = {4},
issn = {1520-5207},
address = {Washington, DC},
publisher = {Soc.},
reportid = {FZJ-2014-00997},
pages = {1003 - 1011},
year = {2014},
abstract = {It is generally accepted that oligomers of aggregating
proteins play an important role in the onset of
neurodegenerative diseases. While in silico aggregation
studies of full length amyloidogenic proteins are
computationally expensive, the assembly of short protein
fragments derived from these proteins with similar
aggregating properties has been extensively studied. In the
present work, molecular dynamics simulations are performed
to follow peptide aggregation on the microsecond time scale.
By defining aggregation states, we identify transition
networks, disconnectivity graphs, and first passage time
distributions to describe the kinetics of the assembly
process. This approach unravels differences in the
aggregation into hexamers of two peptides with different
primary structures. The first is GNNQQNY, a hydrophilic
fragment from the prion protein Sup35, and the second is
KLVFFAE, a fragment from amyloid-β protein, with a
hydrophobic core delimited by two charged amino acids. The
assembly of GNNQQNY suggests a mechanism of monomer
addition, with a bias toward parallel peptide pairs and a
gradual increase in the amount of β-strand content. For
KLVFFAE, a mechanism involving dimers rather than monomers
is revealed, involving a generally higher β-strand content
and a transition toward a larger number of antiparallel
peptide pairs during the rearrangement of the hexamer. The
differences observed for the aggregation of the two peptides
suggests the existence of a sequence-aggregation
relationship.},
cin = {ICS-6},
ddc = {530},
cid = {I:(DE-Juel1)ICS-6-20110106},
pnm = {452 - Structural Biology (POF2-452)},
pid = {G:(DE-HGF)POF2-452},
typ = {PUB:(DE-HGF)16},
UT = {WOS:000330610400016},
pubmed = {pmid:24401100},
doi = {10.1021/jp412648u},
url = {https://juser.fz-juelich.de/record/150966},
}