Molecules,
Год журнала:
2023,
Номер
28(7), С. 2886 - 2886
Опубликована: Март 23, 2023
G12
mutations
heavily
affect
conformational
transformation
and
activity
of
KRAS.
In
this
study,
Gaussian
accelerated
molecular
dynamics
(GaMD)
simulations
were
performed
on
the
GDP-bound
wild-type
(WT),
G12A,
G12D,
G12R
KRAS
to
probe
mutation-mediated
impacts
alterations
The
results
indicate
that
three
obviously
structural
flexibility
internal
switch
domains.
analyses
free
energy
landscapes
(FELs)
suggest
induce
more
states
lead
disordered
principal
component
analysis
shows
change
concerted
motions
behavior
domains
mostly
overlap
with
binding
region
its
effectors.
Thus,
high
disorder
motion
changes
induced
by
interaction
network
GDP
signifies
instability
in
interactions
magnesium
ion
domain
SW1
drives
state
This
work
is
expected
provide
theoretical
aids
for
understanding
function
Journal of Biomolecular Structure and Dynamics,
Год журнала:
2025,
Номер
unknown, С. 1 - 11
Опубликована: Май 27, 2025
The
Src
homology-2
(SH2)-containing
phosphatase
2
(SHP2),
a
non-receptor
protein
tyrosine
phosphatase,
is
key
regulator
modulating
various
signaling
pathways.
Recent
studies
have
revealed
that
phosphorylation
of
Tyr62
(pY62)
on
the
N-SH2
domain
SHP2
causes
emergence
acquired
resistance
to
allosteric
inhibitor
(SHP099)
occupies
PTP
catalytic
domain.
However,
mechanism
underlying
insensitivity
SHP099
phosphorylated
(pSHP2)
remains
unexplored.
In
this
study,
multiple
replica
molecular
dynamics
(MD)
simulations
and
post-trajectory
analyses
(principal
component
analysis,
cross-correlation
matrix
community
binding
free
energy
calculations)
were
performed
for
SHP2,
pSHP2,
SHP2-SHP099,
pSHP2-SHP099
complexes.
MD
results
showed
contributed
stabilize
but
pY62
had
detrimental
role
in
stability
complex.
Domain
correlation
analysis
increased
anti-correlated
motions
between
C-SH2
N-SH2/PTP
domains.
Binding
calculations
protein-ligand
interactions
-
complex
stronger
than
pSHP2
Further,
Thr108,
Phe113,
Glu250
might
be
critical
residues
responsible
loss
affinity
through
per-residue
decomposition
H-bond
occupancy
time
analysis.
Overall,
study
may
provide
mechanistic
insight
into
how
effect
binding.
Journal of Biomolecular Structure and Dynamics,
Год журнала:
2023,
Номер
42(7), С. 3363 - 3381
Опубликована: Май 22, 2023
Point
mutations
play
a
vital
role
in
the
conformational
transformation
of
HRAS.
In
this
work,
Gaussian
accelerated
molecular
dynamics
(GaMD)
simulations
followed
by
constructions
free
energy
landscapes
(FELs)
were
adopted
to
explore
effect
D33K,
A59T
and
L120A
on
conformation
states
GDP-bound
The
results
from
post-processing
analyses
GaMD
trajectories
suggest
that
alter
flexibility
motion
modes
switch
domains
FELs
show
induce
more
disordered
affect
interactions
GDP
with
HRAS,
implying
yield
binding
HRAS
effectors.
GDP-residue
interaction
network
revealed
our
current
work
indicates
salt
bridges
hydrogen
bonding
(HBIs)
key
roles
Furthermore,
instability
magnesium
ions
SI
leads
extreme
disorder
domains.
This
study
is
expected
provide
energetic
basis
mechanism
for
further
understanding
function
HRAS.Communicated
Ramaswamy
H.
Sarma
Molecules,
Год журнала:
2023,
Номер
28(7), С. 2886 - 2886
Опубликована: Март 23, 2023
G12
mutations
heavily
affect
conformational
transformation
and
activity
of
KRAS.
In
this
study,
Gaussian
accelerated
molecular
dynamics
(GaMD)
simulations
were
performed
on
the
GDP-bound
wild-type
(WT),
G12A,
G12D,
G12R
KRAS
to
probe
mutation-mediated
impacts
alterations
The
results
indicate
that
three
obviously
structural
flexibility
internal
switch
domains.
analyses
free
energy
landscapes
(FELs)
suggest
induce
more
states
lead
disordered
principal
component
analysis
shows
change
concerted
motions
behavior
domains
mostly
overlap
with
binding
region
its
effectors.
Thus,
high
disorder
motion
changes
induced
by
interaction
network
GDP
signifies
instability
in
interactions
magnesium
ion
domain
SW1
drives
state
This
work
is
expected
provide
theoretical
aids
for
understanding
function
