Computational Analysis of the Fully Activated Orexin Receptor 2 across Various Thermodynamic Ensembles with Surface Tension Monitoring and Markov State Modeling
The Journal of Physical Chemistry B,
Год журнала:
2025,
Номер
unknown
Опубликована: Фев. 11, 2025
In
this
study,
we
investigated
the
stability
of
fully
activated
conformation
orexin
receptor
2
(OX2R)
embedded
in
a
pure
POPC
bilayer
using
MD
simulations.
Various
thermodynamic
ensembles
(i.e.,
NPT,
NVT,
NVE,
NPAT,
μVT,
and
NPγT)
were
employed
to
explore
dynamical
heterogeneity
system
comprehensive
way.
addition,
informational
similarity
metrics
(e.g.,
Jensen-Shannon
divergence)
as
well
Markov
state
modeling
approaches
utilized
elucidate
kinetics.
Special
attention
was
paid
assessing
surface
tension
within
simulation
box,
particularly
under
NPγT
conditions,
where
21
nominal
constants
evaluated.
Our
findings
suggest
that
traditional
such
NPT
may
not
adequately
control
physical
properties
membrane,
impacting
plausibility
OX2R
model.
general,
performed
study
underscores
importance
employing
ensemble
for
computational
investigations
membrane-embedded
receptors,
it
effectively
maintains
zero
simulated
system.
These
results
offer
valuable
insights
future
research
aimed
at
understanding
dynamics
designing
targeted
therapeutics.
Язык: Английский
Allosteric Communication Mechanism in the Glucagon Receptor
Journal of Biological Chemistry,
Год журнала:
2025,
Номер
301(6), С. 108530 - 108530
Опубликована: Апрель 23, 2025
Recent
drug
development
suggests
agonists
may
be
more
promising
against
glucagon
receptor
dysregulation
in
metabolic
disorders.
Allosteric
modulation
pave
an
alternative
way
to
initiate
responses
that
are
required
target
these
Here,
we
investigated
the
allosteric
communication
mechanisms
within
using
molecular
dynamics
simulations
on
five
states.
Results
highlighted
extracellular
domain
is
dynamic
absence
of
orthosteric
agonist.
In
presence
a
partial
agonist,
observed
increased
flexibility
N
terminus
compared
with
full
agonist-bound
receptor.
Class
B1
G
protein-coupled
(GPCR)
microswitches
showed
repacking
going
from
inactive
state
active
state,
allowing
for
protein
coupling.
agonist-
and
protein-bound
Gαs
both
translational
rotational
movement
terminus,
core,
α5-helix,
thereby
forming
key
interactions
between
core
Finally,
region
coupling
was
strongest
intracellular
negative
modulator-bound
agonist
protein-free
state.
The
residue
positions
predicted
play
significant
role
mechanism
overlap
disease-associated
mutations.
Overall,
our
study
provides
insights
into
class
GPCR,
which
sets
foundation
future
design
modulators
targeting
Язык: Английский
Insights into the structure and activation mechanism of some class B1 GPCR family members
Molecular Biology Reports,
Год журнала:
2024,
Номер
51(1)
Опубликована: Сен. 6, 2024
Язык: Английский
Molecular Mechanisms Underlying the Loop-Closing Dynamics of β-1,4 Galactosyltransferase 1
Journal of Chemical Information and Modeling,
Год журнала:
2024,
Номер
65(1), С. 390 - 401
Опубликована: Дек. 31, 2024
The
β-1,4
galactosylation
catalyzed
by
galactosyltransferases
(β4Gal-Ts)
is
not
only
closely
associated
with
diverse
physiological
and
pathological
processes
in
humans
but
also
widely
applied
the
N-glycan
modification
of
protein
glycoengineering.
loop-closing
process
β4Gal-Ts
an
essential
intermediate
step
intervening
binding
events
donor
substrate
(UDP-Gal/Mn2+)
acceptor
during
its
catalytic
cycle,
a
significant
impact
on
activities.
However,
molecular
mechanisms
regulating
dynamics
are
entirely
clear.
Here,
we
construct
Markov
state
models
(MSMs)
based
approximately
20
μs
all-atom
simulations
to
explore
for
galactosyltransferase
1
(β4Gal-T1).
Our
MSM
reveals
five
key
metastable
states
β4Gal-T1
upon
binding,
indicating
that
entire
conformational
transition
occurs
time
scale
∼10
μs.
Moreover,
regulatory
mechanism
involving
six
conserved
residues
(R187,
H190,
F222,
W310,
I341,
D346)
among
validated
account
C-loop
W-loop
site-directed
mutagenesis
enzymatic
activity
assays,
exhibiting
high
consistency
our
computational
predictions.
Overall,
research
proposes
detailed
atomic-level
insight
into
β4Gal-T1,
contributing
deeper
understanding
galactosylation.
Язык: Английский
Deepening insights into cholinergic agents for intraocular pressure reduction: systems genetics, molecular modeling, and in vivo perspectives
Frontiers in Molecular Biosciences,
Год журнала:
2024,
Номер
11
Опубликована: Июль 26, 2024
Parasympathetic
activation
in
the
anterior
eye
segment
regulates
various
physiological
functions.
This
process,
mediated
by
muscarinic
acetylcholine
receptors,
also
impacts
intraocular
pressure
(IOP)
through
trabecular
meshwork.
While
FDA-approved
M3
receptor
(M3R)
agonists
exist
for
IOP
reduction,
their
systemic
cholinergic
adverse
effects
pose
limitations
clinical
use.
Therefore,
advancing
our
understanding
of
system
is
crucial
developing
additional
IOP-reducing
agents
with
improved
safety
profiles.
Systems
genetics
analyses
were
utilized
to
explore
correlations
between
and
five
major
subtypes.
Molecular
docking
dynamics
simulations
applied
human
M3R
homology
model
using
a
comprehensive
set
ligands
1,667
or
investigational
drugs.
Lead
compounds
from
modeling
studies
then
tested
IOP-lowering
abilities
mice.
unveiled
positive
mRNA
expressions
among
subtypes,
negative
correlation
observed
only
IOP.
Through
studies,
rivastigmine
edrophonium
emerged
as
most
optimally
suited
drugs
reducing
via
potentially
distinct
mechanism
pilocarpine
physostigmine.
Subsequent
animal
confirmed
comparable
reductions
rivastigmine,
edrophonium,
pilocarpine,
longer
durations
action
edrophonium.
Mild
but
absent
These
findings
advance
ocular
therapeutics,
suggesting
more
nuanced
role
parasympathetic
than
previously
thought.
Язык: Английский
Efficient Delivering of a Photodynamic Therapy Drug into Cellular Membranes Rationalized by Molecular Dynamics
The Journal of Physical Chemistry B,
Год журнала:
2024,
Номер
128(47), С. 11625 - 11633
Опубликована: Ноя. 13, 2024
Photodynamic
therapy
(PDT)
represents
a
most
attractive
therapeutic
strategy
to
reduce
side-effects
of
chemotherapy
and
improve
the
global
quality
life
patients.
Yet,
many
PDT
drugs
suffer
from
poor
bioavailability
cellular
intake,
thus,
drug-delivering
strategies
are
mandatory.
In
this
article,
we
rationalize
behavior
temoporfin-based
drug,
commercialized
under
name
Foscan,
complexed
by
two
β-cyclodextrin
units,
acting
as
drug
carriers,
in
presence
lipid
bilayer.
Our
all-atom
simulations
have
unequivocally
shown
internalization
complex
suggest
its
possible
spontaneous
dissociation
bilayer
core.
The
factors
favoring
penetration
also
been
analyzed,
together
with
membrane
perturbation
due
interaction
carrier
complex.
results
confirm
suitability
encapsulation
for
experimental
concerning
efficacy.
Язык: Английский