bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Июнь 12, 2024
ABSTRACT
Protein
post-translational
modifications,
such
as
phosphorylation,
are
important
regulatory
signals
for
diverse
cellular
functions.
In
particular,
intrinsically
disordered
protein
regions
(IDRs)
subject
to
phosphorylation
a
means
modulate
their
interactions
and
Toward
understanding
the
relationship
between
in
IDRs
specific
functional
outcomes,
we
must
consider
how
affects
IDR
conformational
ensemble.
Various
experimental
techniques
suited
interrogate
features
of
ensembles;
molecular
simulations
can
provide
complementary
insights
even
illuminate
ensemble
that
may
be
experimentally
inaccessible.
Therefore,
sought
expand
tools
available
study
phosphorylated
by
all-atom
Monte
Carlo
simulations.
To
this
end,
implemented
parameters
phosphoserine
(pSer)
phosphothreonine
(pThr)
into
OPLS
version
continuum
solvent
model,
ABSINTH,
assessed
performance
compared
published
findings.
We
simulated
short
(<
20
residues)
long
(>
80
phospho-IDRs
that,
collectively,
survey
both
local
global
phosphorylation-induced
changes
Our
four
well-studied
show
near-quantitative
agreement
with
findings
these
systems
via
metrics
including
radius
gyration,
transient
helicity,
persistence
length.
also
leveraged
inherent
advantage
sequence
control
explore
effects
combinations
phospho-sites
two
multi-phosphorylated
IDRs.
results
support
on
prior
observations
connect
Herein,
describe
alter
chemistry,
net
charge
patterning,
intramolecular
interactions,
which
collectively
features.
SIGNIFICANCE
Spatially
temporally
controlled
is
critical
many
facets
function
broader
health.
Intrinsically
overrepresented
targets
but
structural
consequences
modifications
remain
elusive
systems.
rigorous
modeling
using
simulations,
present
new
ABSINTH
implicit
paradigm.
Through
example
phospho-IDRs,
demonstrate
excellent
our
phospho-IDR
datasets.
ACS Physical Chemistry Au,
Год журнала:
2024,
Номер
5(1), С. 17 - 29
Опубликована: Ноя. 13, 2024
In-droplet
hydrogen/deuterium
exchange
(HDX)-mass
spectrometry
(MS)
experiments
have
been
conducted
for
peptides
of
highly
varied
conformational
type.
A
new
model
is
presented
that
combines
the
use
protection
factors
(PF)
from
molecular
dynamics
(MD)
simulations
with
intrinsic
HDX
rates
(kint)
to
obtain
a
structure-to-reactivity
calibration
curve.
Using
model,
relationship
peptide
structural
flexibility
and
reactivity
different
elucidated.
Additionally,
used
describe
degree
bias
disease-relevant
Nt17
peptide;
although
flexible,
intrinsically
primed
facile
conversion
α-helical
conformation
upon
binding
partners
imparts
significant
in-droplet
this
peptide.
In
future,
scale
may
be
developed
whereby
predictive
(propensity
form
2°
elements
such
as
α-helix,
β-sheet,
β-turn)
disordered
regions
(IDRs).
Such
resolution
ultimately
high-throughput
screening
IDR
transformation(s)
ligands
drug
candidates.
Biophysical Journal,
Год журнала:
2024,
Номер
unknown
Опубликована: Ноя. 1, 2024
Protein
post-translational
modifications,
such
as
phosphorylation,
are
important
regulatory
signals
for
diverse
cellular
functions.
In
particular,
intrinsically
disordered
protein
regions
(IDRs)
subject
to
phosphorylation
a
means
modulate
their
interactions
and
Toward
understanding
the
relationship
between
in
IDRs
specific
functional
outcomes,
we
must
consider
how
affects
IDR
conformational
ensemble.
Various
experimental
techniques
suited
interrogate
features
of
ensembles;
molecular
simulations
can
provide
complementary
insights
even
illuminate
ensemble
that
may
be
experimentally
inaccessible.
Therefore,
sought
expand
tools
available
study
phosphorylated
by
all-atom
Monte
Carlo
simulations.
To
this
end,
implemented
parameters
phosphoserine
(pSer)
phosphothreonine
(pThr)
into
OPLS
version
continuum
solvent
model,
ABSINTH,
assessed
performance
compared
with
published
findings.
We
simulated
short
(<20
residues)
long
(>80
phospho-IDRs
that,
collectively,
survey
both
local
global
phosphorylation-induced
changes
Our
four
well-studied
show
near-quantitative
agreement
findings
these
systems
via
metrics
including
radius
gyration,
transient
helicity,
persistence
length.
also
leveraged
inherent
advantage
sequence
control
explore
effects
combinations
phospho-sites
two
multiphosphorylated
IDRs.
results
support
on
previous
observations
connect
Herein,
describe
alter
chemistry,
net
charge
patterning,
intramolecular
interactions,
which
collectively
features.
JACS Au,
Год журнала:
2024,
Номер
4(12), С. 4729 - 4743
Опубликована: Ноя. 14, 2024
It
has
become
increasingly
evident
that
the
conformational
distributions
of
intrinsically
disordered
proteins
or
regions
are
strongly
dependent
on
their
amino
acid
compositions
and
sequence.
To
facilitate
a
systematic
investigation
these
sequence-ensemble
relationships,
we
selected
set
16
naturally
occurring
identical
length
but
with
large
differences
in
composition,
hydrophobicity,
charge
patterning.
We
probed
ensembles
single-molecule
Förster
resonance
energy
transfer
(FRET),
complemented
by
circular
dichroism
(CD)
nuclear
magnetic
(NMR)
spectroscopy
as
well
small-angle
X-ray
scattering
(SAXS).
The
shows
strong
dependence
chain
dimensions
sequence
volumes
differing
up
to
factor
6.
residue-specific
intrachain
interaction
networks
underlie
pronounced
were
identified
using
atomistic
simulations
combined
ensemble
reweighting,
revealing
important
role
charged,
aromatic,
polar
residues.
advance
transferable
description
protein
regions,
further
employed
experimental
data
parametrize
coarse-grained
model
for
includes
an
explicit
representation
FRET
fluorophores
successfully
describes
experiments
different
dye
pairs.
Our
findings
demonstrate
value
integrating
advancing
our
quantitative
understanding
features
determine
proteins.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Июнь 12, 2024
ABSTRACT
Protein
post-translational
modifications,
such
as
phosphorylation,
are
important
regulatory
signals
for
diverse
cellular
functions.
In
particular,
intrinsically
disordered
protein
regions
(IDRs)
subject
to
phosphorylation
a
means
modulate
their
interactions
and
Toward
understanding
the
relationship
between
in
IDRs
specific
functional
outcomes,
we
must
consider
how
affects
IDR
conformational
ensemble.
Various
experimental
techniques
suited
interrogate
features
of
ensembles;
molecular
simulations
can
provide
complementary
insights
even
illuminate
ensemble
that
may
be
experimentally
inaccessible.
Therefore,
sought
expand
tools
available
study
phosphorylated
by
all-atom
Monte
Carlo
simulations.
To
this
end,
implemented
parameters
phosphoserine
(pSer)
phosphothreonine
(pThr)
into
OPLS
version
continuum
solvent
model,
ABSINTH,
assessed
performance
compared
published
findings.
We
simulated
short
(<
20
residues)
long
(>
80
phospho-IDRs
that,
collectively,
survey
both
local
global
phosphorylation-induced
changes
Our
four
well-studied
show
near-quantitative
agreement
with
findings
these
systems
via
metrics
including
radius
gyration,
transient
helicity,
persistence
length.
also
leveraged
inherent
advantage
sequence
control
explore
effects
combinations
phospho-sites
two
multi-phosphorylated
IDRs.
results
support
on
prior
observations
connect
Herein,
describe
alter
chemistry,
net
charge
patterning,
intramolecular
interactions,
which
collectively
features.
SIGNIFICANCE
Spatially
temporally
controlled
is
critical
many
facets
function
broader
health.
Intrinsically
overrepresented
targets
but
structural
consequences
modifications
remain
elusive
systems.
rigorous
modeling
using
simulations,
present
new
ABSINTH
implicit
paradigm.
Through
example
phospho-IDRs,
demonstrate
excellent
our
phospho-IDR
datasets.