bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2023,
Volume and Issue:
unknown
Published: Aug. 24, 2023
Hydroxynitrile
lyase
from
rubber
tree
(HbHNL)
shares
45%
identical
amino
acid
residues
with
the
homologous
esterase
tobacco,
SABP2,
but
two
enzymes
catalyze
different
reactions.
The
x-ray
structures
reveal
a
serine-histidine-aspartate
catalytic
triad
in
both
along
several
differing
within
active
site.
Previous
exchange
of
three
site
HbHNL
corresponding
residue
SABP2
(T11G-E79H-K236M)
created
variant
HNL3,
which
showed
low
activity
toward
p-nitrophenyl
acetate.
Further
structure
comparison
reveals
additional
differences
surrounding
contains
an
improperly
positioned
oxyanion
hole
and
solvation
aspartate.
We
hypothesized
that
correcting
these
structural
would
impart
good
on
variant.
To
predict
substitutions
needed
to
correct
structure,
we
calculated
shortest
path
maps
for
correlated
movements
acids
enzymes.
Replacing
four
(C81L-N104T-V106F-G176S)
whose
are
connected
yielded
HNL7TV
(stabilizing
substitution
H103V
was
also
added),
efficiency
comparable
SABP2.
intermediate
variant,
HNL6V,
altered
aspartate
partially
corrected
hole.
This
dramatic
increase
demonstrates
ability
outside
contribute
activity.
Science,
Journal Year:
2023,
Volume and Issue:
382(6673)
Published: Nov. 23, 2023
Biocatalysis
harnesses
enzymes
to
make
valuable
products.
This
green
technology
is
used
in
countless
applications
from
bench
scale
industrial
production
and
allows
practitioners
access
complex
organic
molecules,
often
with
fewer
synthetic
steps
reduced
waste.
The
last
decade
has
seen
an
explosion
the
development
of
experimental
computational
tools
tailor
enzymatic
properties,
equipping
enzyme
engineers
ability
create
biocatalysts
that
perform
reactions
not
present
nature.
By
using
(chemo)-enzymatic
synthesis
routes
or
orchestrating
intricate
cascades,
scientists
can
synthesize
elaborate
targets
ranging
DNA
pharmaceuticals
starch
made
vitro
CO2-derived
methanol.
In
addition,
new
chemistries
have
emerged
through
combination
biocatalysis
transition
metal
catalysis,
photocatalysis,
electrocatalysis.
review
highlights
recent
key
developments,
identifies
current
limitations,
provides
a
future
prospect
for
this
rapidly
developing
technology.
ACS Omega,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Feb. 8, 2024
Understanding
enzyme
mechanisms
is
essential
for
unraveling
the
complex
molecular
machinery
of
life.
In
this
review,
we
survey
field
computational
enzymology,
highlighting
key
principles
governing
and
discussing
ongoing
challenges
promising
advances.
Over
years,
computer
simulations
have
become
indispensable
in
study
mechanisms,
with
integration
experimental
exploration
now
established
as
a
holistic
approach
to
gain
deep
insights
into
enzymatic
catalysis.
Numerous
studies
demonstrated
power
characterizing
reaction
pathways,
transition
states,
substrate
selectivity,
product
distribution,
dynamic
conformational
changes
various
enzymes.
Nevertheless,
significant
remain
investigating
multistep
reactions,
large-scale
changes,
allosteric
regulation.
Beyond
mechanistic
studies,
modeling
has
emerged
an
tool
computer-aided
design
rational
discovery
covalent
drugs
targeted
therapies.
Overall,
design/engineering
drug
development
can
greatly
benefit
from
our
understanding
detailed
enzymes,
such
protein
dynamics,
entropy
contributions,
allostery,
revealed
by
studies.
Such
convergence
different
research
approaches
expected
continue,
creating
synergies
research.
This
outlining
ever-expanding
research,
aims
provide
guidance
future
directions
facilitate
new
developments
important
evolving
field.
Proceedings of the National Academy of Sciences,
Journal Year:
2024,
Volume and Issue:
121(34)
Published: Aug. 12, 2024
Two
years
on
from
the
initial
release
of
AlphaFold,
we
have
seen
its
widespread
adoption
as
a
structure
prediction
tool.
Here,
discuss
some
latest
work
based
with
particular
focus
use
within
structural
biology
community.
This
encompasses
cases
like
speeding
up
determination
itself,
enabling
new
computational
studies,
and
building
tools
workflows.
We
also
look
at
ongoing
validation
predictions
continue
to
be
compared
against
large
numbers
experimental
structures
further
delineate
model’s
capabilities
limitations.
Faraday Discussions,
Journal Year:
2024,
Volume and Issue:
252, P. 306 - 322
Published: Jan. 1, 2024
It
is
challenging
to
identify
enzyme
mutations
that
enhance
specific
conformational
changes.We
develop
the
shortest
path
map
method
address
this
challenge.
Journal of the American Chemical Society,
Journal Year:
2024,
Volume and Issue:
146(24), P. 16670 - 16680
Published: June 7, 2024
To
unravel
why
computational
design
fails
in
creating
viable
enzymes,
while
directed
evolution
(DE)
succeeds,
our
research
delves
into
the
laboratory
of
protoglobin.
DE
has
adapted
this
protein
to
efficiently
catalyze
carbene
transfer
reactions.
We
show
that
previously
proposed
enhanced
substrate
access
and
binding
alone
cannot
account
for
increased
yields
during
DE.
The
3D
electric
field
entire
active
site
is
tracked
through
dynamics,
clustered
using
affinity
propagation
algorithm,
subjected
principal
component
analysis.
This
analysis
reveals
notable
changes
with
DE,
where
distinct
topologies
influence
transition
state
energetics
mechanism.
A
chemically
meaningful
emerges
takes
lead
facilitates
crossing
barrier
transfer.
Our
findings
underscore
intrinsic
dynamic's
on
enzyme
function,
ability
switch
mechanisms
within
same
protein,
crucial
role
design.
Journal of Chemical Theory and Computation,
Journal Year:
2024,
Volume and Issue:
20(12), P. 5317 - 5336
Published: June 12, 2024
Despite
the
success
of
AlphaFold
methods
in
predicting
single
protein
structures,
these
showed
intrinsic
limitations
characterization
multiple
functional
conformations
allosteric
proteins.
The
recent
NMR-based
structural
determination
unbound
ABL
kinase
active
state
and
discovery
inactive
low-populated
that
are
unique
for
present
an
ideal
challenge
AlphaFold2
approaches.
In
current
study,
we
employ
several
adaptations
methodology
to
predict
conformational
ensembles
states
including
randomized
alanine
sequence
scanning
combined
with
alignment
subsampling
proposed
this
study.
We
show
new
adaptation
local
frustration
profiling
enables
accurate
prediction
structures
ensembles,
also
offering
a
robust
approach
interpretable
predictions
detection
hidden
states.
found
large
high
residue
clusters
uniquely
characteristic
low-populated,
fully
form
can
define
energetically
frustrated
cracking
sites
transitions,
presenting
difficult
targets
AlphaFold2.
results
study
uncovered
previously
unappreciated
fundamental
connections
between
profiles
ability
This
integration
landscape-based
analysis
allows
atomistic
providing
physical
basis
successes
detecting
play
significant
role
regulation.
Acta Pharmaceutica Sinica B,
Journal Year:
2024,
Volume and Issue:
14(11), P. 4806 - 4818
Published: Aug. 27, 2024
TROP-2,
a
tumor-associated
antigen,
has
been
implicated
in
the
progression
of
various
epithelial
tumors.
Due
to
its
favorable
expression
profile,
TROP-2
emerged
as
promising
target
for
antibody–drug
conjugates
(ADCs)
based
anti-tumor
therapies.
Although
ADCs
have
shown
efficacy
cancer
treatment,
their
application
solid
tumors
is
hindered
by
high
molecular
weight,
poor
tumor
penetration,
and
release
cytotoxic
molecules.
Therefore,
recombinant
immunotoxin
was
developed
on
shark-derived
variable
domain
immunoglobulin
new
antigen
receptor
(VNAR)
antibody.
VNARs
are
only
one-tenth
size
IgG
antibodies
possess
remarkable
tissue
penetration
capabilities
stability.
In
this
study,
shark
VNAR
phage
display
library
created,
leading
identification
VNAR-5G8
that
targets
TROP-2.
exhibited
affinity
cellular
internalization
ability
towards
cells
expressing
levels
Epitope
analysis
revealed
recognizes
hidden
epitope
consisting
CRD
TY-1
Subsequently,
fused
with
truncated
form
Pseudomonas
exotoxin
(PE38)
create
(5G8-PE38),
which
significant
activity
vitro
vivo.
Overall,
study
highlights
promise
5G8-PE38
valuable
candidate
therapy.
Journal of Flow Chemistry,
Journal Year:
2023,
Volume and Issue:
14(1), P. 211 - 218
Published: Oct. 23, 2023
Abstract
Flow
biocatalysis
has
emerged
as
an
empowering
tool
to
boost
the
potential
of
enzymatic
reactions
towards
more
automatized,
sustainable,
and
generally
efficient
synthetic
processes.
In
last
fifteen
years,
increasing
number
biocatalytic
transformations
carried
out
in
continuous
flow
exemplified
benefits
that
this
technology
can
bring
incorporate
into
industrial
operations.
This
perspective
aims
capture
a
nutshell
available
methodologies
for
well
discuss
current
limitations
future
directions
field.
Graphical
abstract
Chemical Communications,
Journal Year:
2023,
Volume and Issue:
60(6), P. 632 - 645
Published: Dec. 7, 2023
Proposed
de
novo
peptide
design
strategy
against
amyloidogenic
targets.
After
initial
computational
preparation
of
the
binder
and
target,
experimental
validation
are
incorporated
in
iterative
machine
learning
powered
cycles
to
generate
better
improved
peptide-based