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(22), P. 8616 - 8627
Published: Nov. 6, 2024
Emerging
evidence
suggests
that
physiological
C-terminal
truncation
of
α-synuclein
(αS)
plays
a
critical
role
in
regulating
liquid-liquid
phase
separation
and
promoting
amyloid
aggregation,
processes
implicated
neurodegenerative
diseases
such
as
Parkinson's
disease
(PD).
However,
the
molecular
mechanisms
through
which
influences
αS
conformation
modulates
its
aggregation
remain
poorly
understood.
In
this
study,
we
investigated
impact
on
conformational
dynamics
by
comparing
full-length
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.
