Assessing the mechanism of fast‐cycling cancer‐associated mutations of Rac1 small Rho GTPase
Protein Science,
Journal Year:
2024,
Volume and Issue:
33(4)
Published: March 19, 2024
Rho-GTPases
proteins
function
as
molecular
switches
alternating
from
an
active
to
inactive
state
upon
Guanosine
triphosphate
(GTP)
binding
and
hydrolysis
diphosphate
(GDP).
Among
them,
Rac
subfamily
regulates
cell
dynamics,
being
overexpressed
in
distinct
cancer
types.
Notably,
these
are
object
of
frequent
cancer-associated
mutations
at
Pro29
(P29S,
P29L,
P29Q).
To
assess
the
impact
on
Rac1
structure
function,
we
performed
extensive
all-atom
dynamics
simulations
wild-type
(wt)
oncogenic
isoforms
this
protein
GDP-
GTP-bound
states.
Our
results
unprecedentedly
elucidate
that
P29Q/S-induced
structural
dynamical
perturbations
core
domain
weaken
catalytic
site
Mg
Language: Английский
Viral RNA Replication Suppression of SARS-CoV-2: Atomistic Insights into Inhibition Mechanisms of RdRp Machinery by ddhCTP
Journal of Chemical Information and Modeling,
Journal Year:
2024,
Volume and Issue:
64(5), P. 1593 - 1604
Published: Feb. 27, 2024
The
nonstructural
protein
12,
known
as
RNA-dependent
RNA
polymerase
(RdRp),
is
essential
for
both
replication
and
repair
of
the
viral
genome.
RdRp
SARS-CoV-2
has
been
used
a
promising
candidate
drug
development
since
inception
COVID-19
spread.
In
this
work,
we
performed
an
Language: Английский
On the dual role of (+)-catechin as primary antioxidant and inhibitor of viral proteases
Computers in Biology and Medicine,
Journal Year:
2024,
Volume and Issue:
180, P. 108953 - 108953
Published: July 31, 2024
Natural
antioxidants
have
become
the
subject
of
many
investigations
due
to
role
that
they
play
in
reduction
oxidative
stress.
Their
main
scavenging
mechanisms
concern
direct
inactivation
free
radicals
and
coordination
metal
ions
involved
Fenton-like
reactions.
Recently,
increasing
attention
has
been
paid
non-covalent
inhibition
enzymes
different
diseases
by
antioxidants.
Here,
a
computational
investigation
on
primary
antioxidant
power
(+)-catechin
against
Language: Английский
On the Role of Temperature in the Depolymerization of PET by FAST‐PETase: An Atomistic Point of View on Possible Active Site Pre‐Organization and Substrate‐Destabilization Effects
ChemBioChem,
Journal Year:
2023,
Volume and Issue:
24(20)
Published: Aug. 9, 2023
Enzyme
FAST-PETase,
recently
obtained
by
a
machine
learning
approach,
can
depolymerize
poly(ethylene
terephthalate)
(PET),
synthetic
resin
employed
in
plastics
and
clothing
fibers.
Therefore
it
represents
promising
solution
for
the
recycling
of
PET-based
materials.
In
this
study,
model
PET
was
adopted
to
describe
substrate,
all-atoms
classical
molecular
dynamics
(MD)
simulations
on
apo-
substrate-bound
FAST-PETase
were
carried
out
at
30
50
°C
provide
atomistic
details
binding
step
catalytic
cycle.
Comparative
analysis
shed
light
interactions
occurring
between
4PET
°C,
optimal
working
conditions
enzyme.
Pre-organization
enzyme
active
sites
has
been
highlighted,
while
MD
FAST-PETase:4PET
pointed
occurrence
solvent-inaccessible
conformations
substrate
promoted
Indeed,
neither
these
observed
during
alone
performed
30,
150
°C.
The
led
us
propose
that,
is
pre-organized
bind
that
site
promote
more
reactive
conformation
thus
enhancing
activity
Language: Английский
Incorporation of N7-Platinated Guanines into Thermus Aquaticus (Taq) DNA Polymerase: Atomistic Insights from Molecular Dynamics Simulations
International Journal of Molecular Sciences,
Journal Year:
2023,
Volume and Issue:
24(12), P. 9849 - 9849
Published: June 7, 2023
In
this
work,
we
elucidated
some
key
aspects
of
the
mechanism
action
cisplatin
anticancer
drug,
cis-[Pt(NH3)2Cl2],
involving
direct
interactions
with
free
nucleotides.
A
comprehensive
in
silico
molecular
modeling
analysis
was
conducted
to
compare
Thermus
aquaticus
(Taq)
DNA
polymerase
three
distinct
N7-platinated
deoxyguanosine
triphosphates:
[Pt(dien)(N7-dGTP)]
(1),
cis-[Pt(NH3)2Cl(N7-dGTP)]
(2),
and
cis-[Pt(NH3)2(H2O)(N7-dGTP)]
(3)
{dien
=
diethylenetriamine;
dGTP
5'-(2'-deoxy)-guanosine-triphosphate},
using
canonical
as
a
reference,
presence
DNA.
The
goal
elucidate
binding
site
between
Taq
tested
nucleotide
derivatives,
providing
valuable
atomistic
insights.
Unbiased
dynamics
simulations
(200
ns
for
each
complex)
explicit
water
molecules
were
performed
on
four
ternary
complexes,
yielding
significant
findings
that
contribute
better
understanding
experimental
results.
highlighted
crucial
role
specific
α-helix
(O-helix)
within
fingers
subdomain,
which
facilitates
proper
geometry
functional
contacts
incoming
template
needed
incorporation
into
polymerase.
revealed
complex
1
exhibits
much
lower
affinity
than
complexes
2-3.
affinities
metabolites
2-3
found
be
quite
similar
those
natural
dGTP,
resulting
rate
compared
These
could
have
implications
action,
high
intracellular
availability
nucleobases
might
promote
competitive
platinated
nucleotides
over
attachment
study's
insights
active
suggest
may
been
previously
underestimated.
Language: Английский
Trapping a non-cognate nucleotide upon initial binding for replication fidelity control in SARS-CoV-2 RNA dependent RNA polymerase
Physical Chemistry Chemical Physics,
Journal Year:
2023,
Volume and Issue:
26(3), P. 1792 - 1808
Published: Dec. 11, 2023
The
RNA
dependent
polymerase
(RdRp)
in
SARS-CoV-2
is
a
highly
conserved
enzyme
responsible
for
viral
genome
replication/transcription.
To
understand
how
the
RdRp
achieves
fidelity
control
during
such
processes,
here
we
computationally
investigate
natural
non-cognate
Language: Английский
Flavone Derivatives as Potential Inhibitors of SARS-Cov-2rdrp through Computational Studies
Mohammed Merzouki,
No information about this author
Ayoub Bekkouch,
No information about this author
Raed Alkowni
No information about this author
et al.
Journal Of Biochemical Technology,
Journal Year:
2023,
Volume and Issue:
14(4), P. 74 - 82
Published: Jan. 1, 2023
The
objective
of
this
study
is
to
identify
potential
targets
within
the
SARS-CoV-2
RdRp
for
discovery
novel
inhibitors
derived
from
therapeutic
natural
compounds
sourced
aromatic
and
medicinal
plants.
In
course
study,
a
library
was
generated
containing
five
naturally
occurring
flavone
derivatives
(4a,
4b,
4c,
4d,
4e)
in
conjunction
with
standard
favipiravir-RTP.
underwent
an
in-silico
methodology
involving
critical
steps,
including
(a)
evaluating
ADM
Language: Английский
Molecular Dynamics and QM/MM to Understand Genome Organization and Reproduction in Emerging RNA Viruses
Elsevier eBooks,
Journal Year:
2023,
Volume and Issue:
unknown, P. 895 - 909
Published: April 27, 2023
Language: Английский
Trapping non-cognate nucleotide upon initial binding for replication fidelity control in SARS-CoV-2 RNA dependent RNA polymerase
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2023,
Volume and Issue:
unknown
Published: Sept. 4, 2023
Abstract
The
RNA
dependent
polymerase
(RdRp)
in
SARS-CoV-2
is
a
highly
conserved
enzyme
responsible
for
viral
genome
replication/transcription.
Here
we
investigate
computationally
natural
non-cognate
vs
cognate
nucleotide
addition
cycle
(NAC)
and
intrinsic
selectivity
during
the
RdRp
elongation,
focusing
prechemically
from
initial
substrate
binding
(enzyme
active
site
open)
to
insertion
(active
closed)
of
contrast
with
one-step
only
process.
Current
studies
have
been
first
carried
out
using
microsecond
ensemble
equilibrium
all-atom
molecular
dynamics
(MD)
simulations.
Due
slow
conformational
changes
(from
open
accompanying
selection,
enhanced
or
umbrella
sampling
methods
further
employed
calculate
free
energy
profiles
NTP
insertion.
Our
show
notable
stability
noncognate
dATP
GTP
upon
active-site
state.
results
indicate
that
while
ATP
Remdesivir
drug
analogue
(RDV-TP)
are
biased
be
stabilized
closed
state,
can
well
trapped
off-path
configurations.
work
thus
presents
an
mechanism
fidelity
control
replication.
Language: Английский