Journal of Chemical Information and Modeling,
Journal Year:
2024,
Volume and Issue:
64(22), P. 8604 - 8615
Published: Nov. 8, 2024
Pathological
aggregation
of
essentially
dissociated
Transthyretin
(TTR)
monomer
proteins,
driven
by
misfolding
and
self-interaction,
is
associated
with
amyloidosis
(ATTR)
disease.
The
TTR
proteins
consist
several
fragments
that
tend
to
self-aggregate.
Recent
experimental
studies
showed
the
sequence
residues
TTR91–96
plays
an
important
role
in
self-aggregation.
However,
mechanisms
underlying
monomers
are
still
unknown.
In
this
study,
we
used
microsecond
molecular
dynamics
simulations
investigate
self-assembly
Octamers.
We
also
investigated
E92P
V94P
mutants
for
comparative
analysis.
analysis
indicates
hydrophobic
interactions
π–π
stacking
patterns
play
roles
reducing
β-sheet
content
mutants.
Additionally,
our
findings
reveal
conformational
transition
octamer
from
closed
β-barrel,
open
β-barrel
β-bilayer
aggregation.
further
elucidate
dynamic
mechanism
intermediate
states
stable
states.
Overall,
research
may
contribute
development
drug
design
combat
fibrous
amyloid
diseases.
Journal of Chemical Information and Modeling,
Journal Year:
2024,
Volume and Issue:
64(13), P. 5303 - 5316
Published: June 26, 2024
The
coexistence
of
amyloid-β
(Aβ)
and
human
islet
amyloid
polypeptide
(hIAPP)
in
the
brain
pancreas
is
associated
with
an
increased
risk
Alzheimer's
disease
(AD)
type
2
diabetes
(T2D)
due
to
their
coaggregation
cross-seeding.
Despite
this,
molecular
mechanisms
underlying
interaction
remain
elusive.
Here,
we
systematically
investigated
cross-talk
between
Aβ
hIAPP
using
atomistic
discrete
dynamics
(DMD)
simulations.
Our
results
revealed
that
amyloidogenic
core
regions
both
(Aβ
Journal of Chemical Information and Modeling,
Journal Year:
2024,
Volume and Issue:
64(11), P. 4500 - 4510
Published: May 15, 2024
Human
calcitonin
(hCT)
regulates
calcium-phosphorus
metabolism,
but
its
amyloid
aggregation
disrupts
physiological
activity,
increases
thyroid
carcinoma
risk,
and
hampers
clinical
use
for
bone-related
diseases
like
osteoporosis
Paget's
disease.
Improving
hCT
with
targeted
modifications
to
mitigate
formation
while
maintaining
function
holds
promise
as
a
strategy.
Understanding
how
each
residue
in
hCT's
amyloidogenic
core
affects
structure
dynamics
is
crucial
designing
effective
analogues.
Mutants
F16L-hCT
F19L-hCT,
where
Phe
residues
the
are
replaced
Leu
nonamyloidogenic
salmon
calcitonin,
showed
different
kinetics.
However,
molecular
effects
of
these
substitutions
still
unclear.
Here,
we
systematically
investigated
folding
self-assembly
conformational
hCT,
F16L-hCT,
F19L-hCT
through
multiple
long-time
scale
independent
atomistic
discrete
(DMD)
simulations.
Our
results
indicated
that
monomer
primarily
assumed
unstructured
conformations
dynamic
helices
around
4-12
14-21.
During
self-assembly,
Journal of Chemical Information and Modeling,
Journal Year:
2024,
Volume and Issue:
64(20), P. 8024 - 8033
Published: Oct. 9, 2024
The
aggregation
of
amyloid-β
(Aβ)
into
amyloid
fibrils
is
the
major
pathological
hallmark
Alzheimer's
disease
(AD).
Aβ
can
adopt
a
variety
morphologies,
relative
populations
which
are
recently
found
to
be
associated
with
different
AD
subtypes
such
as
familial
and
sporadic
(fAD
sAD,
respectively).
two
differ
in
their
ages
onset,
AD-related
genetic
predispositions,
dominant
fibril
morphologies.
We
postulate
that
these
subtype-dependent
morphology
differences
attributed
intrinsic
properties
interacting
molecules
environment.
Using
atomistic
discrete
molecular
dynamics
simulations,
we
demonstrated
fAD-dominant
exhibited
lower
free-energy
barrier
for
growth
but
also
stability
compared
sAD-dominant
morphology,
resulting
time-dependent
population
change
consistent
experimental
observations.
Additionally,
studied
effect
Bri2
BRICHOS
domain,
an
endogenous
protein
has
been
reported
inhibit
by
preferential
binding
fibrils,
one
possible
environmental
factors.
domain
showed
stronger
than
silico,
suggesting
more
effective
suppression
formation.
This
result
explains
high
cases
normal
functions.
Genetic
predisposition
fAD,
on
other
hand,
might
impair
or
overwhelm
functions,
leading
fAD-associated
morphology.
Together,
our
computational
findings
provide
theoretical
framework
elucidating
entailed
distinct
Nature Communications,
Journal Year:
2025,
Volume and Issue:
16(1)
Published: March 26, 2025
The
amyloid
hypothesis
has
been
a
leading
narrative
concerning
the
pathophysiological
foundation
of
Alzheimer's
and
Parkinson's
disease.
At
two
ends
lie
functional
protein
monomers
pathology-defining
fibrils,
while
early
stages
aggregation
are
populated
by
polymorphic,
transient
neurotoxic
oligomers.
As
structure
activity
oligomers
intertwined,
here
we
show
arising
from
liquid-liquid
phase
separation
β-barrel
formation,
their
routes
to
neurodegeneration,
role
in
cerebrovascular
perturbation.
Together,
this
Perspective
converges
on
multifaceted
oligomer-axis
central
pathological
origin
and,
hence,
treatment
diseases.
For
decades,
research
disease
dementia
lacked
unified
framework.
This
explores
convergence
key
oligomerization
processes
that
drive
neurodegeneration
damage,
aiming
advance
effective
diagnosis
