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@ARTICLE{Liao:830415,
author = {Liao, Qinghua and Owen, Michael and Olubiyi, Olujide and
Barz, Bogdan and Strodel, Birgit},
title = {{C}onformational {T}ransitions of the {A}myloid-β
{P}eptide {U}pon {C}opper({II}) {B}inding and p{H}
{C}hanges},
journal = {Israel journal of chemistry},
volume = {57},
number = {7-8},
issn = {0021-2148},
address = {Weinheim},
publisher = {Wiley-VCH},
reportid = {FZJ-2017-03964},
pages = {771–784},
year = {2017},
abstract = {Amyloid-β (Aβ) is a natively unfolded peptide found in
all Alzheimer's disease patients as the major component of
fibrillar plaques, which are recognized as an important
pathological hallmark in Alzheimer's disease. The binding of
copper to Aβ increases its neurotoxicity, as Cu2+ causes
Aβ to become redox active and decreases the lag time
associated with Aβ aggregation. In addition, the pH is a
major factor that influences both the Aβ aggregation rates
and Cu2+ binding. Hamiltonian replica exchange molecular
dynamics (H-REMD) simulations enable atomistic insights into
the effects of pH and Cu2+ complexation on the structure and
dynamics of Aβ. To study the Aβ1–42/Cu2+ complex, we
have developed new force-field parameters for the divalent
copper ion ligated by the two histidine residues, His6 and
His13, as well as the amine and carbonyl groups of Asp1, in
a distorted square-planar geometry. Our comparative
simulations reveal that both Cu2+ binding and a low
pH-mimicking acidosis, linked to inflammatory processes
in vivo, accelerate the formation of β-strands in
Aβ1–42 and lead to the stabilization of salt bridges,
previously shown to promote Aβ aggregation. The results
suggest that Cu2+ binding and mild acidic conditions can
shift the conformational equilibrium towards
aggregation-prone conformers for the monomeric Aβ.},
cin = {ICS-6},
ddc = {540},
cid = {I:(DE-Juel1)ICS-6-20110106},
pnm = {553 - Physical Basis of Diseases (POF3-553)},
pid = {G:(DE-HGF)POF3-553},
typ = {PUB:(DE-HGF)16},
UT = {WOS:000407253500019},
doi = {10.1002/ijch.201600108},
url = {https://juser.fz-juelich.de/record/830415},
}