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Pleomorphic ensembles: formation of large clusters composed of weakly interacting multivalent molecules.
[wiskott-aldrich syndrome]
Molecular
interactions
of
importance
to
cell
biology
are
subject
to
sol
-gel
transitions
:
large
clusters
of
weakly
interacting
multivalent
molecules
(
gel
phase
)
are
produced
at
a
critical
concentration
of
monomers
.
Examples
include
cell-cell
and
cell-matrix
adhesions
,
nucleoprotein
bodies
,
and
cell
signaling
platforms
.
We
use
the
term
pleomorphic
ensembles
(
PEs
)
to
describe
these
clusters
,
because
they
have
dynamic
compositions
and
sizes
and
have
rapid
turnover
of
their
molecular
constituents
;
this
plasticity
can
be
highly
responsive
to
cellular
signals
.
The
classical
polymer
physical
chemistry
theory
developed
by
Flory
and
Stockmayer
provides
a
brilliant
framework
for
treating
multivalent
interactions
for
simple
idealized
systems
.
But
the
complexity
and
variability
of
PEs
challenges
existing
modeling
approaches
.
Here
we
describe
and
validate
a
computational
algorithm
that
extends
the
Flory-
Stockmayer
formalism
to
overcome
the
limitations
of
analytic
theories
.
We
divide
the
problem
by
deterministically
calculating
the
fraction
of
bound
sites
for
each
type
of
binding
site
,
followed
by
the
stochastic
assignment
of
the
bonds
to
a
finite
number
of
molecules
.
The
method
allows
for
high
valency
within
many
different
kinds
of
interacting
molecules
and
site
types
,
permits
simulation
of
steady-
state
distributions
,
as
well
as
assembly
kinetics
,
and
can
treat
cooperative
binding
within
one
of
the
interacting
molecules
.
We
then
apply
our
method
to
the
analysis
of
interactions
in
the
nephrin-
Nck-
N-Wasp
signaling
system
,
demonstrating
how
multivalent
layered
scaffolds
produce
PEs
at
low
monomer
concentrations
despite
weak
binding
interactions
.
We
show
how
the
experimental
data
for
this
system
are
most
consistent
with
synergistic
cooperative
interactions
between
Nck
and
N-Wasp
.
Diseases
Validation
Diseases presenting
"bound sites for each type of binding site"
symptom
wiskott-aldrich syndrome
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