Conformations of KRAS4B Affected by Its Partner Binding and G12C Mutation: Insights from GaMD Trajectory-Image Transformation-Based Deep Learning
Journal of Chemical Information and Modeling,
Год журнала:
2024,
Номер
64(17), С. 6880 - 6898
Опубликована: Авг. 28, 2024
Binding
of
partners
and
mutations
highly
affects
the
conformational
dynamics
KRAS4B,
which
is
significance
for
deeply
understanding
its
function.
Gaussian
accelerated
molecular
(GaMD)
simulations
followed
by
deep
learning
(DL)
principal
component
analysis
(PCA)
were
carried
out
to
probe
effect
G12C
binding
three
NF1,
RAF1,
SOS1
on
conformation
alterations
KRAS4B.
DL
reveals
that
result
in
contacts
key
structure
domains,
such
as
switch
domains
SW1
SW2
together
with
loops
L4,
L5,
P-loop.
constrains
structural
fluctuation
SW1,
SW2,
L5;
contrary,
leads
instability
these
four
domains.
The
analyses
free
energy
landscapes
(FELs)
PCA
also
show
maintains
stability
states
KRAS4B
while
induces
greater
mobility
produces
significant
impacts
interactions
GTP
L5.
Our
findings
suggest
partner
play
important
roles
activity
allosteric
regulation
may
theoretically
aid
further
function
Язык: Английский
Molecular Mechanism of Phosphorylation-Mediated Impacts on the Conformation Dynamics of GTP-Bound KRAS Probed by GaMD Trajectory-Based Deep Learning
Molecules,
Год журнала:
2024,
Номер
29(10), С. 2317 - 2317
Опубликована: Май 15, 2024
The
phosphorylation
of
different
sites
produces
a
significant
effect
on
the
conformational
dynamics
KRAS.
Gaussian
accelerated
molecular
(GaMD)
simulations
were
combined
with
deep
learning
(DL)
to
explore
mechanism
phosphorylation-mediated
GTP-bound
DL
finds
that
switch
domains
are
involved
in
obvious
differences
conformation
contacts
and
suggests
play
key
role
function
analyses
free
energy
landscapes
(FELs)
reveal
pY32,
pY64,
pY137
leads
more
disordered
states
than
wild-type
(WT)
KRAS
induces
transformations
between
closed
open
states.
results
from
principal
component
analysis
(PCA)
indicate
motions
PC1
PC2
responsible
for
phosphorylated
Interaction
networks
analyzed
verify
alters
interactions
GTP
magnesium
ion
Mg
Язык: Английский
QM/MM study reveals novel mechanism of KRAS and KRASG12R catalyzed GTP hydrolysis
International Journal of Biological Macromolecules,
Год журнала:
2025,
Номер
297, С. 139820 - 139820
Опубликована: Янв. 11, 2025
Язык: Английский
Mechanism of Regio- and Enantioselective Hydroxylation of Arachidonic Acid Catalyzed by Human CYP2E1: A Combined Molecular Dynamics and Quantum Mechanics/Molecular Mechanics Study
Journal of Chemical Information and Modeling,
Год журнала:
2025,
Номер
unknown
Опубликована: Фев. 11, 2025
Regio-
and
enantioselective
hydroxylation
of
free
fatty
acids
by
human
cytochrome
P450
2E1
(CYP2E1)
plays
an
important
role
in
metabolic
regulation
has
significant
pathological
implications.
Despite
extensive
research,
the
detailed
mechanism
CYP2E1
remains
incompletely
understood.
To
clarify
origins
regioselectivity
enantioselectivity
observed
for
CYP2E1-mediated
acid
hydroxylation,
molecular
dynamics
(MD)
simulations
quantum
mechanics/molecular
mechanics
(QM/MM)
calculations
were
performed.
MD
provided
key
insights
into
proximity
arachidonic
acid's
carbon
atoms
to
reactive
iron(IV)-oxo
moiety
compound
I
(Cpd
I),
with
ω-1
position
being
closest,
indicating
higher
reactivity
at
this
site.
QM/MM
identified
hydrogen
abstraction
as
rate-determining
step,
ω-1S
transition
state
exhibiting
lowest
energy
barrier,
consistent
experimentally
enantioselectivity.
Energy
decomposition
analysis
revealed
that
variations
mechanical
(ΔEQM)
significantly
influence
reaction
barriers,
most
efficient
occurring
ω-2R
positions.
These
findings
underscore
importance
substrate
positioning
within
active
site
determining
product
selectivity.
Comparisons
two
related
P450s,
P450BM3
P450SPα,
further
highlighted
critical
architecture
modulating
While
surrounding
residues
do
not
directly
dictate
selectivity,
they
shape
environment
positioning.
Furthermore,
our
a
previously
unrecognized
catalytic
Ala299.
provide
deeper
mechanistic
understanding
offer
valuable
its
precise
engineering
targeted
C-H
functionalization.
Язык: Английский
Molecular Dynamics Investigation into the Stability of KRas and CRaf Multimeric Complexes
The Journal of Physical Chemistry B,
Год журнала:
2025,
Номер
unknown
Опубликована: Март 24, 2025
In
the
Ras/Raf/MAPK
signaling
pathway,
Ras
and
Raf
proteins
interact
synergistically
to
form
a
tetrameric
complex.
NMR
experiments
have
demonstrated
that
dimerizes
in
solution
binds
stably
Raf,
forming
Ras·Raf
complexes.
this
study,
we
constructed
ternary
quaternary
complexes
of
KRas
CRaf
based
on
crystal
structures,
denoted
as
(KRas)2·CRaf
(KRas)2·(CRaf)2,
respectively.
Molecular
dynamics
(MD)
simulations
were
performed
investigate
stability
these
complexes,
while
hydrogen
bonds
well
salt
bridges
formed
at
protein–protein
interaction
interfaces
analyzed
simulation
trajectories.
The
results
revealed
KRas·CRaf
complex
is
more
stable
explicit
solvent
compared
with
dimer.
Formation
(KRas)2·(CRaf)2
might
be
attributed
association
two
binary
Additionally,
MD
KRasG12D·CRaf
extended
binding
site
KRas–CRaf
interface.
This
was
identified
potential
therapeutic
target
block
abnormal
signal
transmission
pathway.
Язык: Английский
Activity Regulation and Conformation Response of Janus Kinase 3 Mediated by Phosphorylation: Exploration from Correlation Network Analysis and Markov Model
Journal of Chemical Information and Modeling,
Год журнала:
2025,
Номер
unknown
Опубликована: Апрель 8, 2025
The
activity
of
the
enzyme
JAK3
is
modulated
by
tyrosine
phosphorylation,
yet
underlying
molecular
details
remain
not
fully
understood.
In
this
study,
we
employed
a
GaMD
trajectory-based
Markov
model
and
correlation
network
analysis
(CNA)
to
investigate
impact
single
phosphorylation
(SP)
at
Y980
(pY980)
double
(DP)
Y980/Y981
(pY980/pY981)
on
conformational
dynamics
bound
inhibitors
IZA
MI1.
indicated
that
both
SP
DP
result
in
fewer
states
significantly
influence
P-loop,
αC-helix,
loop1-loop3,
while
maintaining
hinge
region's
high
rigidity.
CNA
findings
revealed
alters
communication
among
different
structural
regions
JAK3,
providing
rational
explanation
for
how
affects
distant
P-loop
loop1-loop3.
Moreover,
changes
mediated
further
affect
interactions
between
hot
spots
(L828,
V836,
E903,
Y904,
L905,
L956)
JAK3.
This
work
offers
valuable
theoretical
insights
into
mechanisms
regulate
activity.
Язык: Английский
Development of Accurate Forces for Mg2+ and Triphosphate Interactions in ATP·Mg2+ and GTP·Mg2+ Complexes
Journal of Chemical Theory and Computation,
Год журнала:
2024,
Номер
unknown
Опубликована: Ноя. 21, 2024
In
cells,
adenosine
triphosphate
(ATP)
and
guanosine
(GTP)
molecules
typically
form
tricoordinated
or
bicoordinated
ATP·Mg
Язык: Английский