Viruses,
Journal Year:
2023,
Volume and Issue:
15(10), P. 2009 - 2009
Published: Sept. 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.
Physical Chemistry Chemical Physics,
Journal Year:
2023,
Volume and Issue:
25(32), P. 21245 - 21266
Published: Jan. 1, 2023
In
this
study,
we
systematically
examine
the
conformational
dynamics,
binding
and
allosteric
communications
in
Omicron
BA.1,
BA.2,
BA.3
BA.4/BA.5
spike
protein
complexes
with
ACE2
host
receptor
using
molecular
dynamics
simulations
perturbation-based
network
profiling
approaches.
Microsecond
atomistic
provided
a
detailed
characterization
of
landscapes
revealed
increased
thermodynamic
stabilization
BA.2
variant
which
can
be
contrasted
variants
inducing
significant
mobility
complexes.
Using
dynamics-based
mutational
scanning
residues,
identified
structural
stability
affinity
hotspots
Perturbation
response
network-based
approaches
probed
effect
mutations
on
interactions
The
results
analysis
specific
roles
as
conformationally
plastic
evolutionary
adaptable
modulators
allostery
are
coupled
to
major
regulatory
positions
through
interaction
networks.
Through
perturbation
residue
potentials
performed
background
original
strain,
characterized
regions
epistatic
couplings
that
centered
around
N501Y
Q498R.
Our
dissected
vital
role
these
centers
regulating
stability,
efficient
allows
for
accumulation
multiple
immune
escape
at
other
sites.
integrative
computational
approaches,
study
provides
systematic
effects
thermodynamics,
signaling
receptor.
Journal of Chemical Information and Modeling,
Journal Year:
2021,
Volume and Issue:
61(10), P. 5172 - 5191
Published: Sept. 22, 2021
We
developed
a
computational
framework
for
comprehensive
and
rapid
mutational
scanning
of
binding
energetics
residue
interaction
networks
in
the
SARS-CoV-2
spike
protein
complexes.
Using
this
approach,
we
integrated
atomistic
simulations
conformational
landscaping
complexes
with
ensemble-based
screening
network
modeling
to
characterize
mechanisms
structure–functional
mimicry
resilience
toward
escape
by
ACE2
decoy
de
novo
designed
miniprotein
inhibitors.
A
detailed
analysis
structural
plasticity
proteins
obtained
from
landscapes
sequence-based
profiling
disorder
propensities
revealed
intrinsically
flexible
regions
that
harbor
key
functional
sites
targeted
circulating
variants.
The
conservation
collective
dynamics
showed
positions
are
important
modulation
motions
changes
these
can
alter
allosteric
networks.
Through
complexes,
identified
regulatory
hotspots
collectively
determine
response
miniproteins
results
suggest
affinities
signatures
be
determined
dynamic
crosstalk
between
structurally
stable
centers
conformationally
adaptable
control
escape.
This
may
underlie
mechanism
which
moderate
perturbations
induce
global
modulating
signaling
International Journal of Molecular Sciences,
Journal Year:
2022,
Volume and Issue:
23(19), P. 11542 - 11542
Published: Sept. 29, 2022
In
this
study,
we
performed
all-atom
MD
simulations
of
RBD-ACE2
complexes
for
BA.1,
BA.1.1,
BA.2,
and
BA.3
Omicron
subvariants,
conducted
a
systematic
mutational
scanning
the
binding
interfaces
analysis
electrostatic
effects.
The
free
energy
computations
comprehensive
examination
interactions
quantify
driving
forces
provide
new
insights
into
energetic
mechanisms
underlying
evolutionary
differences
between
variants.
A
RBD
residues
determines
protein
stability
centers
hotpots
in
complexes.
By
employing
ensemble-based
global
network
analysis,
propose
community-based
topological
model
that
characterized
functional
roles
sites
mediating
non-additive
epistatic
effects
mutations.
Our
findings
suggest
contributions
to
affinity
may
be
mediated
by
R493,
Y498,
Y501
are
greater
BA.1.1
BA.2
display
strongest
ACE2
among
subvariants.
network-centric
adaptation
reversed
allosteric
communication
is
unveiled
which
established
robust
connection
hotspots
potential
pockets.
Using
approach,
demonstrated
long-range
could
anchor
experimentally
validated
Through
an
array
complementary
approaches
proposed
models,
multi-faceted
computational
study
revealed
quantified
multiple
key
site
R498,
acting
as
hotspots,
drivers
well
mediators
communications
with
Physical Chemistry Chemical Physics,
Journal Year:
2024,
Volume and Issue:
26(25), P. 17720 - 17744
Published: Jan. 1, 2024
In
this
study,
we
combined
AlphaFold-based
approaches
for
atomistic
modeling
of
multiple
protein
states
and
microsecond
molecular
simulations
to
accurately
characterize
conformational
ensembles
evolution
binding
mechanisms
convergent
the
SARS-CoV-2
spike
Omicron
variants
BA.1,
BA.2,
BA.2.75,
BA.3,
BA.4/BA.5
BQ.1.1.
We
employed
validated
several
different
adaptations
AlphaFold
methodology
including
introduced
randomized
full
sequence
scanning
manipulation
variations
systematically
explore
dynamics
complexes
with
ACE2
receptor.
Microsecond
(MD)
provide
a
detailed
characterization
landscapes
thermodynamic
stability
variant
complexes.
By
integrating
predictions
from
applying
statistical
confidence
metrics
can
expand
identify
functional
conformations
that
determine
equilibrium
ACE2.
Conformational
RBD-ACE2
obtained
using
MD
are
accurate
comparative
prediction
energetics
revealing
an
excellent
agreement
experimental
data.
particular,
results
demonstrated
AlphaFold-generated
extended
produce
energies
The
study
suggested
complementarities
potential
synergies
between
showing
information
both
methods
potentially
yield
more
adequate
This
provides
insights
in
interplay
binding,
through
acquisition
mutational
sites
may
leverage
adaptability
dynamic
couplings
key
energy
hotspots
optimize
affinity
enable
immune
evasion.
International Journal of Molecular Sciences,
Journal Year:
2022,
Volume and Issue:
23(8), P. 4376 - 4376
Published: April 15, 2022
In
this
study,
we
combine
all-atom
MD
simulations
and
comprehensive
mutational
scanning
of
S-RBD
complexes
with
the
angiotensin-converting
enzyme
2
(ACE2)
host
receptor
in
native
form
as
well
Delta
Omicron
variants
to
(a)
examine
differences
dynamic
signatures
(b)
identify
critical
binding
hotspots
sensitivity
positions.
We
also
examined
allosteric
interactions
communications
for
variants.
Through
perturbation-based
propensities
SARS-CoV-2
residues
dynamics-based
network
centrality
community
analyses,
characterize
global
mediating
centers
nature
local
stabilizing
communities.
show
that
a
constellation
sites
(G496S,
Q498R,
N501Y
Y505H)
correspond
key
energy
contribute
decisively
interfacial
communities
mediate
between
ACE2.
These
mutations
are
responsible
both
favorable
long-range
interactions,
providing
functional
high
transmissibility
virus.
At
same
time,
our
results
other
could
provide
“flexible
shield”
surrounding
stable
network,
thereby
allowing
virus
modulate
immune
evasion
at
different
epitopes,
while
protecting
integrity
RBD–ACE2
complexes.
This
study
suggests
S
protein
may
exploit
plasticity
RBD
generate
escape
mutants,
engaging
small
group
efficient
International Journal of Molecular Sciences,
Journal Year:
2022,
Volume and Issue:
23(6), P. 2928 - 2928
Published: March 8, 2022
Nanobodies
provide
important
advantages
over
traditional
antibodies,
including
their
smaller
size
and
robust
biochemical
properties
such
as
high
thermal
stability,
solubility,
the
ability
to
be
bioengineered
into
novel
multivalent,
multi-specific,
high-affinity
molecules,
making
them
a
class
of
emerging
powerful
therapies
against
SARS-CoV-2.
Recent
research
efforts
on
design,
protein
engineering,
structure-functional
characterization
nanobodies
binding
with
SARS-CoV-2
S
proteins
reflected
growing
realization
that
nanobody
combinations
can
exploit
distinct
epitopes
leverage
intrinsic
plasticity
conformational
landscape
for
produce
efficient
neutralizing
mutation
resistant
characteristics.
Structural
computational
studies
have
also
been
instrumental
in
quantifying
structure,
dynamics,
energetics
spike
nanobodies.
In
this
review,
comprehensive
analysis
current
structural,
biophysical,
biology
investigations
complexes
classes
targeting
different
sites
is
presented.
The
supplemented
by
an
in-depth
examination
mutational
scanning
simulations
identification
energy
hotspots
classes.
review
focused
mechanisms
underlying
synergistic
multivalent
superior
single
conventional
cocktails
combating
escape
mutations
effectively
leveraging
avidity
allosteric
cooperativity.
We
discuss
how
structural
insights
engineering
approaches
together
tools
aid
rational
design
exhibit
neutralization
characteristics
owing
avidity-mediated
mechanisms.
Journal of Chemical Information and Modeling,
Journal Year:
2024,
Volume and Issue:
64(5), P. 1657 - 1681
Published: Feb. 19, 2024
The
latest
wave
of
SARS-CoV-2
Omicron
variants
displayed
a
growth
advantage
and
increased
viral
fitness
through
convergent
evolution
functional
hotspots
that
work
synchronously
to
balance
requirements
for
productive
receptor
binding
efficient
immune
evasion.
In
this
study,
we
combined
AlphaFold2-based
structural
modeling
approaches
with
atomistic
simulations
mutational
profiling
energetics
stability
prediction
comprehensive
analysis
the
structure,
dynamics,
BA.2.86
spike
variant
ACE2
host
distinct
classes
antibodies.
We
adapted
several
AlphaFold2
predict
both
structure
conformational
ensembles
protein
in
complex
receptor.
results
showed
AlphaFold2-predicted
ensemble
can
accurately
capture
main
states
variant.
Complementary
predictions,
microsecond
molecular
dynamics
reveal
details
landscape
produced
equilibrium
structures
are
used
perform
scanning
residues
characterize
energy
hotspots.
ensemble-based
domain
BA.2
complexes
revealed
group
conserved
hydrophobic
critical
variant-specific
contributions
R403K,
F486P,
R493Q.
To
examine
evasion
properties
detail,
performed
structure-based
interfaces
antibodies
significantly
reduced
neutralization
against
basis
compensatory
effects
hotspots,
showing
lineage
may
have
evolved
outcompete
other
subvariants
by
improving
while
preserving
affinity
via
effect
R493Q
F486P
This
study
demonstrated
an
integrative
approach
combining
predictions
complementary
robust
enable
accurate
characterization
mechanisms
newly
emerging
variants.
International Journal of Molecular Sciences,
Journal Year:
2024,
Volume and Issue:
25(9), P. 4955 - 4955
Published: May 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.
Trends in Pharmacological Sciences,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Nov. 1, 2024
Allostery
represents
a
fundamental
mechanism
in
protein
regulation,
enabling
modulation
of
function
from
sites
distal
to
the
active
site.
While
traditionally
explored
context
small
molecules,
allosteric
is
gaining
traction
as
main
mode
action
realm
antibodies,
which
offer
enhanced
specificity
and
reduced
toxicity.
This
review
delves
into
rapidly
growing
field
highlighting
recent
therapeutic
advancements
novel
druggability
avenues.
We
also
explore
potential
these
antibodies
innovative
tools
drug
discovery
discuss
contemporary
strategies
for
designing
leveraging
state-of-the-art
computational
approaches.