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Solvent and mutation effects on the nucleation of amyloid beta-protein folding.
[hereditary cerebral hemorrhage with amyloidosis]
Experimental
evidence
suggests
that
the
folding
and
aggregation
of
the
amyloid
beta
-protein
(
Abeta
)
into
oligomers
is
a
key
pathogenetic
event
in
Alzheimer
's
disease
.
Inhibiting
the
pathologic
folding
and
oligomerization
of
Abeta
could
be
effective
in
the
prevention
and
treatment
of
Alzheimer
's
disease
.
Here
,
using
all-atom
molecular
dynamics
simulations
in
explicit
solvent
,
we
probe
the
initial
stages
of
folding
of
a
decapeptide
segment
of
Abeta
,
Abeta
(
21
-
30
)
,
shown
experimentally
to
nucleate
the
folding
process
.
In
addition
,
we
examine
the
folding
of
a
homologous
decapeptide
containing
an
amino
acid
substitution
linked
to
hereditary
cerebral
hemorrhage
with
amyloidosis
-
Dutch
type
,
[
Gln-
22
]
Abeta
(
21
-
30
)
.
We
find
that
:
(
i
)
when
the
decapeptide
is
in
water
,
hydrophobic
interactions
and
transient
salt
bridges
between
Lys-
28
and
either
Glu-
22
or
Asp-
23
are
important
in
the
formation
of
a
loop
in
the
Val-
24
-
Lys-
28
region
of
the
wild-
type
decapeptide
;
(
ii
)
in
the
presence
of
salt
ions
,
salt
bridges
play
a
more
prominent
role
in
the
stabilization
of
the
loop
;
(
iii
)
in
water
with
a
reduced
density
,
the
decapeptide
forms
a
helix
,
indicating
the
sensitivity
of
folding
to
different
aqueous
environments
;
and
(
iv
)
the
"
Dutch
"
peptide
in
water
,
in
contrast
to
the
wild-
type
peptide
,
fails
to
form
a
long
-lived
Val-
24
-
Lys-
28
loop
,
suggesting
that
loop
stability
is
a
critical
factor
in
determining
whether
Abeta
folds
into
pathologic
structures
.
Diseases
Validation
Diseases presenting
"the sensitivity of folding to different aqueous environments"
symptom
hereditary cerebral hemorrhage with amyloidosis
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