Abstract
Pathological folding and oligomerization of amyloid
$\beta$-protein (A$\beta$) are widely perceived as central to
Alzheimer's disease (AD). A$\beta$ exists in two alloforms,
A$\beta$40 and A$\beta$42, of which A$\beta$42 is linked
particularly strongly to AD. Here we apply a discrete
molecular dynamics approach and a four-bead protein model
with backbone hydrogen bonding and residue-specific effective
hydropathic and electrostatic interactions (EIs) to study
temperature dependence of A$\beta$40 and A$\beta$42 folding
at different strengths of EIs. Our results show that at low
temperatures both A$\beta$40 and A$\beta$42 monomers adopt a
predominantly collapsed--coil conformation with a small
$\alpha$-helical component. At higher temperatures, the
$\beta$-strand structure becomes more prominent in both
alloform. A$\beta$42 monomer conformation is characterized
by a larger number of $\beta$-strands than A$\beta$40
conformation. The temperature dependence of the A$\beta$
folded structure is in a good agreement with recent
experimental findings. At all temperatures,
folded structures of A$\beta$40 and A$\beta$42 show
differences in the N-terminal and C-terminal regions.
The folded A$\beta$42 monomer has an additional turn structure at
the C-terminus not present in A$\beta$40, consistent with
recent in vitro findings. By varying the
strength of EIs, we examine the A$\beta$40 and A$\beta$42
conformational changes due to a change in pH. At the highest
strength of EIs, the folded structures of A$\beta$40 and
A$\beta$42 have the highest amount of $\beta$-strand
structure, while more globular conformations are observed at
the lowest strength of EIs. Our results demonstrate that
A$\beta$ folding is strongly sensitive to both temperature and
pH variations, suggesting a possibility of different aggregation
pathways at slightly different external conditions.
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