bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2023,
Номер
unknown
Опубликована: Сен. 12, 2023
Abstract
In
the
current
study,
we
explore
coarse-grained
simulations
and
atomistic
molecular
dynamics
together
with
binding
energetics
scanning
cryptic
pocket
detection
in
a
comparative
examination
of
conformational
landscapes
systematic
characterization
allosteric
sites
SARS-CoV-2
Omicron
BA.2,
BA.2.75
XBB.1
spike
full-length
trimer
complexes
host
receptor
ACE2.
Microsecond
simulations,
Markov
state
models
mutational
energies
BA.2
domain
revealed
increased
thermodynamic
stabilization
variant
significant
dynamic
differences
between
these
variants.
Molecular
full
length
ACE2
complemented
studies
enabled
an
in-depth
analysis
effects
on
functional
adaptability
Despite
considerable
structural
similarities,
variants
can
induce
unique
signatures
specific
distributions
states.
Using
ensembles
ACE2,
conducted
comprehensive
screening
to
examine
role
mutations
distribution
mechanisms
emerging
sites.
This
captured
all
experimentally
known
discovered
networks
inter-connected
functionally
relevant
that
are
governed
by
variant-sensitive
structures.
The
results
detailed
how
modulate
conserved
druggable
pockets
harboring
important
regions.
for
understanding
roles
be
used
allostery-mediated
therapeutic
intervention
targeting
states
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 28, 2025
Summary
We
report
a
detailed
analysis
of
the
full-length
SARS-CoV-2
spike
dynamics
within
native-like
membrane
environment
and
variants
inaccessible
to
studies
on
soluble
constructs
by
conducting
hydrogen-deuterium
exchange
mass
spectrometry
(HDX-MS)
enveloped
virus-like
particles
(eVLPs)
displaying
various
constructs.
find
that
previously
identified
open-interface
trimer
conformation
is
sampled
in
all
eVLP-displayed
studied
including
sequences
from
engineered
vaccine
native
viral
sequences.
The
D614G
mutation,
which
arose
early
pandemic,
favors
canonical
‘closed-interface’
prefusion
conformation,
potentially
mitigating
premature
S1
shedding
presence
cleaved
furin
site
providing
an
evolutionary
advantage
virus.
Remarkably,
cleavage
at
S1/S2
boundary
allosterically
increases
flexibility
S2’
site,
may
facilitate
increased
TMPRSS2
processing,
enhancing
infectivity.
use
eVLPs
HDX-MS
provides
powerful
platform
for
studying
proteins
near-native
environments.
Frontiers in Molecular Biosciences,
Год журнала:
2023,
Номер
10
Опубликована: Ноя. 2, 2023
Coronavirus
disease
2019
(COVID-19),
caused
by
the
severe
acute
respiratory
syndrome
coronavirus
2
(SARS-CoV-2),
is
a
major
global
health
concern
associated
with
millions
of
fatalities
worldwide.
Mutant
variants
virus
have
further
exacerbated
COVID-19
mortality
and
infection
rates,
emphasizing
urgent
need
for
effective
preventive
strategies.
Understanding
viral
mechanism
crucial
developing
therapeutics
vaccines.
The
entry
SARS-CoV-2
into
host
cells
key
step
in
pathway
has
been
targeted
drug
development.
Despite
numerous
reviews
virus,
there
lack
comprehensive
focusing
on
structural
aspects
entry.
In
this
review,
we
analyze
changes
Spike
proteins
during
process,
dividing
process
prebinding,
receptor
binding,
proteolytic
cleavage,
membrane
fusion
steps.
By
understanding
atomic-scale
details
entry,
can
better
target
intervention
We
also
examine
impacts
mutations
proteins,
including
Omicron
variant,
Structural
information
provides
insights
effects
guide
development
Finally,
discuss
available
structure-based
approaches
Overall,
review
detailed
analysis
highlighting
its
significance
vaccines
against
COVID-19.
Therefore,
our
emphasizes
importance
combating
infection.
International Journal of Molecular Sciences,
Год журнала:
2024,
Номер
25(9), С. 4955 - 4955
Опубликована: Май 1, 2024
Understanding
mechanisms
of
allosteric
regulation
remains
elusive
for
the
SARS-CoV-2
spike
protein,
despite
increasing
interest
and
effort
in
discovering
inhibitors
viral
activity
interactions
with
host
receptor
ACE2.
The
challenges
modulators
proteins
are
associated
diversity
cryptic
sites
complex
molecular
that
can
be
employed
by
ligands,
including
alteration
conformational
equilibrium
protein
preferential
stabilization
specific
functional
states.
In
current
study,
we
combine
dynamics
analysis
distinct
forms
full-length
trimers
machine-learning-based
binding
pocket
detection
ensemble-based
ligand
docking
free
energy
to
characterize
potential
determine
structural
energetic
determinants
inhibition
a
series
experimentally
validated
molecules.
results
demonstrate
good
agreement
between
computational
experimental
affinities,
providing
support
predicted
modes
suggesting
key
formed
ligands
elicit
observed
inhibition.
We
establish
known
molecules,
indicating
mechanism
modulation
targeting
hinges
inter-protomer
movements
blocking
changes
closed
open
trimer
forms.
this
study
combining
states
rigorous
enables
robust
characterization
modes,
identification
hotspots,
prediction
affinities
modulators,
which
is
consistent
data.
This
suggested
adaptability
bound
conformations
both
play
enable
efficient
interfere
changes.
Viruses,
Год журнала:
2023,
Номер
15(10), С. 2009 - 2009
Опубликована: Сен. 27, 2023
A
significant
body
of
experimental
structures
SARS-CoV-2
spike
trimers
for
the
BA.1
and
BA.2
variants
revealed
a
considerable
plasticity
protein
emergence
druggable
binding
pockets.
Understanding
interplay
conformational
dynamics
changes
induced
by
Omicron
identification
cryptic
dynamic
pockets
in
S
is
paramount
importance
as
exploring
broad-spectrum
antiviral
agents
to
combat
emerging
imperative.
In
current
study,
we
explore
landscapes
characterize
universe
multiple
open
closed
functional
states
variants.
By
using
combination
atomistic
simulations,
network
analysis,
an
allostery-guided
screening
ensembles
conformations,
identified
all
experimentally
known
allosteric
sites
discovered
variant-specific
differences
distribution
trimers.
This
study
provided
structural
characterization
predicted
captured
sites,
revealing
critical
role
modulating
cross-talk
between
sites.
We
found
that
mutational
variant
can
induce
remodeling
stabilization
pocket
N-terminal
domain,
while
this
drastically
altered
may
no
longer
be
available
ligand
variant.
Our
results
site
receptor-binding
domain
remains
stable
ranks
most
favorable
but
could
become
fragmented
less
probable
conformations.
also
uncovered
several
formed
at
inter-domain
inter-protomer
interface,
including
regions
S2
subunit
stem
helix
region,
which
are
consistent
with
residues
transitions
antibody
recognition.
The
particularly
understanding
features
proteins,
well
effects
Omicron-variant-specific
modulation
preferential
exploration
present
new
previously
underappreciated
opportunity
therapeutic
interventions
through
conformation-selective
targeting
involved
changes.
Viruses,
Год журнала:
2023,
Номер
15(10), С. 2073 - 2073
Опубликована: Окт. 10, 2023
In
the
current
study,
we
explore
coarse-grained
simulations
and
atomistic
molecular
dynamics
together
with
binding
energetics
scanning
cryptic
pocket
detection
in
a
comparative
examination
of
conformational
landscapes
systematic
characterization
allosteric
sites
SARS-CoV-2
Omicron
BA.2,
BA.2.75
XBB.1
spike
full-length
trimer
complexes
host
receptor
ACE2.
Microsecond
simulations,
Markov
state
models
mutational
energies
BA.2
domain
revealed
increased
thermodynamic
stabilization
variant
significant
dynamic
differences
between
these
variants.
Molecular
ACE2
complemented
studies
enabled
an
in-depth
analysis
effects
on
functional
adaptability
Despite
considerable
structural
similarities,
variants
can
induce
unique
signatures
specific
distributions
states.
Using
ensembles
ACE2,
conducted
comprehensive
screening
to
examine
role
mutations
distribution
mechanisms
emerging
sites.
This
captured
all
experimentally
known
discovered
networks
inter-connected
functionally
relevant
that
are
governed
by
variant-sensitive
structures.
The
results
detailed
how
modulate
conserved
druggable
pockets
harboring
important
regions.
for
understanding
roles
be
used
allostery-mediated
therapeutic
intervention
targeting
states
Biomolecules,
Год журнала:
2023,
Номер
13(7), С. 1130 - 1130
Опубликована: Июль 14, 2023
Viral
entry
and
fertilization
are
distinct
biological
processes
that
share
a
common
mechanism:
membrane
fusion.
In
viral
entry,
enveloped
viruses
attach
to
the
host
cell
membrane,
triggering
series
of
conformational
changes
in
fusion
proteins.
This
results
exposure
hydrophobic
peptide,
which
inserts
into
brings
membranes
close
proximity.
Subsequent
structural
rearrangements
opposing
lead
their
Similarly,
occurs
when
gametes
merge
during
process,
though
exact
mechanism
remains
unclear.
Structural
biology
has
played
pivotal
role
elucidating
molecular
mechanisms
underlying
High-resolution
structures
fusion-related
proteins
have
provided
valuable
insights
occur
this
process.
Understanding
these
at
level
is
essential
for
development
antiviral
therapeutics
tools
influence
fertility.
review,
we
will
highlight
importance
how
protein
helped
visualize
both
elements
subtle
divergences
behind
fusion;
addition,
examine
new
recent
advances
provide
researchers
interested
frame-by-frame
understanding
We
previously
described
a
two-component
protein
nanoparticle
vaccine
platform
that
displays
60
copies
of
the
SARS-CoV-2
spike
RBD
(RBD-NP).
The
vaccine,
when
adjuvanted
with
AS03,
was
shown
to
elicit
robust
neutralizing
antibody
and
CD4
T
cell
responses
in
Phase
I/II
clinical
trials,
met
its
primary
co-endpoints
III
trial,
has
been
licensed
by
multiple
regulatory
authorities
under
brand
name
SKYCovione
