Authorea (Authorea),
Год журнала:
2022,
Номер
unknown
Опубликована: Дек. 15, 2022
Probing
the
structures
of
amyloid-beta
(Aβ)
peptides
in
early
steps
aggregation
is
extremely
difficult
experimentally
and
computationally.
Yet,
this
knowledge
important
as
small
oligomers
are
most
toxic
species.
Experiments
simulations
on
Aβ42
monomer
point
to
random
coil
conformations
with
either
transient
helical
or
β-strand
content.
Our
current
conformational
description
funneled
toward
amorphous
aggregates
some
β-sheet
content
rare
excited
states
well-ordered
assemblies
β-sheets.
In
study,
we
emphasize
another
view
based
metastable
α-helix
bundle
spanning
C-terminus
residues
which
predicted
by
machine-learning
AlphaFold2
method
supported
indirectly
low-resolution
experimental
data
many
amyloid
polypeptides.
This
finding
has
consequences
designing
drugs
reduce
toxicity.
Proteins Structure Function and Bioinformatics,
Год журнала:
2023,
Номер
91(8), С. 1152 - 1162
Опубликована: Май 3, 2023
Abstract
Atomic
characterization
of
large
nonfibrillar
aggregates
amyloid
polypeptides
cannot
be
determined
by
experimental
means.
Starting
from
β‐rich
Y
and
elongated
topologies
predicted
coarse‐grained
simulations
consisting
more
than
100
A
β
16–22
peptides,
we
performed
atomistic
molecular
dynamics
(MD),
replica
exchange
with
solute
scaling
(REST2),
umbrella
sampling
using
the
CHARMM36m
force
field
in
explicit
solvent.
Here,
explored
within
3
μs,
free
energy
landscape,
potential
mean
associated
either
unbinding
one
single
peptide
different
configurations
aggregate
or
fragmentation
events
a
number
peptides.
Within
time
scale
MD
REST2,
find
that
experience
slow
global
conformational
plasticity,
remain
essentially
random
coil
though
observe
beta‐strand
structuring
dominance
antiparallel
beta‐sheets
over
parallel
beta‐sheets.
Enhanced
REST2
simulation
is
able
to
capture
events,
block
peptides
found
similar
fibril
depolymerization
chain
for
longer
sequences.
The
objective
of
this
primer
is
to
discuss
the
chemistry
self-assembly.
It
introduces
some
common
reactions
you
need
know
prepare
a
desired
molecule
that
can
self-assemble
(or
various
molecules
be
mixed
create
self-assembled
system).
focus
on
four
systems
composed
peptides,
peptoids,
sugars,
and
dendrimers.
Authorea (Authorea),
Год журнала:
2022,
Номер
unknown
Опубликована: Дек. 15, 2022
Probing
the
structures
of
amyloid-beta
(Aβ)
peptides
in
early
steps
aggregation
is
extremely
difficult
experimentally
and
computationally.
Yet,
this
knowledge
important
as
small
oligomers
are
most
toxic
species.
Experiments
simulations
on
Aβ42
monomer
point
to
random
coil
conformations
with
either
transient
helical
or
β-strand
content.
Our
current
conformational
description
funneled
toward
amorphous
aggregates
some
β-sheet
content
rare
excited
states
well-ordered
assemblies
β-sheets.
In
study,
we
emphasize
another
view
based
metastable
α-helix
bundle
spanning
C-terminus
residues
which
predicted
by
machine-learning
AlphaFold2
method
supported
indirectly
low-resolution
experimental
data
many
amyloid
polypeptides.
This
finding
has
consequences
designing
drugs
reduce
toxicity.
