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Physical interpretation of microtubule self-organization
in gravitational elds
Jack Tuszynski
a,
, Miljko V. Sataric
a
, Stphanie Portet
a
, John M. Dixon
b
a
Department of Physics, University of Alberta, Edmonton, AB T6G 2J1, Canada
b
Department of Physics, University of Warwick, Coventry CV4 7AL, United Kingdom
Received 24 December 2003; received in revised form 21 November 2004; accepted 29 March 2005
Communicated by A.R. Bishop
Abstract
This Letter discusses the role of key physical and chemical effects in the emergence of pattern formation in microtubule
assemblies in vitro under the inuence of gravity. The roles of chemical kinetics, diffusion, gravitational drift and electrostatic
interactions affected by thermal uctuations are discussed. The subtle interplay of these factors leads to the observed self-
organization phenomena exhibiting the features of a typical polar liquid crystal phase.
2005 Published by Elsevier B.V.
Microtubules (MTs) are the key protein laments
of the cytoskeleton in eukaryotic cells [1] that form
several m long hollow cylinders (typically 25 nm in
diameter) and exhibit dynamically unstable polymer-
ization kinetics combined with substantial structural
rigidity. In the past decade Tabony et al. (TEx) demon-
strated a decisive role of the gravitational force (GF)
in the formation of spatio-temporal patterns by assem-
blies of MTs in vitro [25]. In TEx, MTs were assem-
bled in rectangular spectrometer cells with dimensions
40101 mm
3
by warming puried tubulin (TB) and
GTP in an appropriate buffer solution from 7 to 37

C.
*
Corresponding author.
E-mail address: jtus@phys.ualberta.ca (J. Tuszynski).
The most striking result was obtained with the largest
dimension of the cell (40 mm) parallel to GF leading
to a pattern of stripes of highly oriented MT bundles
(Fig. 1(a)). With the smallest dimension of the cell
(1 mm) parallel to the GF, circular vortex-like mor-
phologies appeared. The critical period for this process
which lasted about 12 hours in [4] or 5 hours in [3,5]
before the equilibrium striped pattern was reached, is
however the rst 6 minutes. If in this period the sam-
ple is subjected to the GF, the characteristic pattern
develops (Fig. 1), while microgravitational conditions
do not lead to pattern formation at all.
The process of MT polymerization from TB is
an example of non-linear chemical kinetics due to
the so-called dynamical instability [1]. The structural
anisotropy of the two MT ends results from an asym-
0375-9601/$ see front matter 2005 Published by Elsevier B.V.
doi:10.1016/j.physleta.2005.03.059
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Fig. 1. (a) During the rst 6 minutes [35] after the onset of assembly, when the largest dimension of the cell (40 mm) is parallel to g, patterns
which we call curtains of highly oriented MTs are developed. The left half of the assembly is at an angle of 45

while the right half is at an

angle of 135

with respect to the horizontal x-axis. (b) The characteristic periodicities developed after 12 hours in [4] or 5 hours in [3,5] within
a single stripe for the samples exposed to GF of g during the rst 10 minutes.
metry of the growing and shrinking processes (the end
+ grows faster than the end that tends to shrink)
and this appears to be correlated with the electrostatic
charge distribution anisotropy [21]. While growth is
gradual, shrinking can take the form of a catastrophe
triggered stochastically by the loss of a GTP lateral
cap [6]. Importantly, in a single event thousands of TB
dimers may be released into solution.
TB dimers are negatively charged globular proteins
that are highly screened by positive counterions of
the solvent. The thermal uctuations of the counter-
charges on TBs cause a van der Waals attractive force
[7] that acts at a short distance and induces the ag-
gregation of TB dimers. We claim that these forces
correlate to initiate catastrophic events enabling TB
dimers to form avalanche correlated clusters (ACC)
which can reach signicant sizes providing conditions
for symmetry breaking due to GF.
A series of experiments on charged biopolymers,
including DNA, F-actin bers and MTs indicate that
in the presence of small amounts of polyvalent salts,
the electrostatic interaction is attractive contradicting
the basic PoissonBoltzmann theory. The attraction
originates from charge uctuations along the rods due
to the exchange between condensed and free counte-
rions. As inter-lament separation decreases, charge
uctuations on one lament couple more strongly with
those on its neighbor. Such is the case in TEx due to
the presence of Mg
2+
ions. In the rst six minutes of
the MT growth process in TEx, the growth rate may
reach V = 1.17 10
7
ms
1
and is isotropic with
the lengths of MTs reaching up to 50 m [8]. MTs
that are this long can affect polymerization kinetics of
their neighbors [9] especially the catastrophe events
which could also initiate polarizational kinks [1012]
propagating along MTs and eventually triggering the
catastrophic shrinking of the lament (Fig. 2). Thus
within a minute several MTs could be depolymerized
into free dimers, packed more tightly than in solution
but less so than in stable MTs.
A single TB dimer has about 40e negative charges
[13]. If only 10% of this charge is unscreened by coun-
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Fig. 2. Massive depolymerization caused by attraction of MTs and
mediated by moving kinks.
terions, then q
eff
= 4e and the Bjerrum length l
B
=
q
2
eff
(4
0
k
B
T )
1
, with = 80 for water, at room
temperature, can reach about 15 nm. This indicates
that two TBs separated by l
B
can be electrostatically
correlated. Thus, if there is sufcient concentration of
TBs from colocalized collapses of MTs, this could
provide the required condition for the appearance of
an ACC.
The Peclet number P
e
[14] relevant for the sedi-
mentation of clusters in a solution is dened as the
ratio of the buoyant energy in the GF and the thermal
energy
(1) P
e
=
m
0
(1 /
0
)gd
k
B
T
,
where m
0
is the cluster mass, g the gravitational ac-
celeration, d the cluster diameter, the density of
solution,
0
the density of the cluster and k
B
T the
thermal energy. For a single TB dimer with a mass
of m
0
= 1.84 10
22
kg and a diameter of roughly
d = 6 nm, the Peclet number at room temperature is
of the order of 10
10
indicating that the gravitational
drift is negligible. For a minimal TB concentration in
water of approximately 10% necessary for ACC with
a diameter of 1 m, we estimate the corresponding
Peclet number as follows. Since ACC is a sponge-
like material with 90% water content, from Eq. (1)
using m
0
=5.4 10
16
kg and /
0
=0.95, we nd
P
e
=0.07 10
1
. This means that drift-led sedimen-
tation of ACCs becomes competitive with an other-
wise dominantly diffusive behavior of TB in solution.
Smaller ACCs are less competitive but still contribute
to the pattern formation in TEx. Drifting along GF
Fig. 3. Left: avalanche-like correlated cluster (ACC) of TB
(d = 1 m) created by catastrophic disassembly events. Right:
showered with rephosphorylated TB, nucleation centers have grown
into highly oriented parallel MTs.
lines, ACCs encounter randomly oriented MT nucle-
ation centers. We propose that sweeping through the
solution ACCs orient their centers so as to initiate a
new MT growth predominantly in the direction of GF
(Fig. 3).
The reactiondiffusiondrift equation for the TB
concentration C(z, t ) around the growing tip of the
MT with the GF directed along the z-axis is derived
from the models of Odde [8] and Prigogine [15] that
account for the specicity of the TEx system
(2) D
2
C +g
C
z
V
C
z
L(z z
0
) =
C
t
.
The rst term above is a diffusion term. The convec-
tion term proportional to g, describes the drift of a
tubulin dimer induced by the GF. The convection term,
proportional to V , is due to the fact that the tip of a
MT, that is xed at the origin, continues to grow at a
relative velocity V . Finally, L(z z
0
), where z
0
is
the length of MT at t =0, describes the initial random
ACCs represented by a spatial step function with asso-
ciated delta-function time correlations.
Extrapolating from the TB diffusion coefcient
for in vivo sea urchin eggs at 25

C as D = 5.9
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10
12
m
2
s
1
[16], we nd D = 70 10
12
m
2
s
1
under the TEx conditions (T = 37

and the viscosity

=10
2
Poise). The GF drift mobility =m
0
D(1

0
)(k
B
T )
1
is quite sensitive to the ACC size. The
rate of MT growth is estimated about V = 1.9
10
7
ms
1
at TEx [6,17].
After a Fourier transformation with respect to z and
t , Eq. (2) leads to the following correlation function
(3)
_
|C
qw
|
2
_
=
|L
qw
|
2

D
2
q
4
+[(g V)q w]
2
,
where q is the wave-number and w is the correspond-
ing frequency. The characteristic relaxation time of the
waves of TB concentration spreading throughout the
TEx cell in the z-direction is given from the disper-
sion relation as
(4) =
2
|q(g V)| +Dq
2
.
From the basic periodicity (A) in the TEx pattern
(Fig. 1(b)), we take the wavelength to be = 3 mm
and estimate =9 10
3
s =2.5 h. This is consistent
with the order of magnitude of the reported time of
5 hours in [3,5] for the development of self-organized
MT patterns.
Solving Eq. (2) for stationary patterns (
C
t
=0) and
for a single growing MT (L = 0), we obtain the z-
dependence of the TB concentration prole
(5) C(z) =C

C
0
exp
_

V g
D
z
_
,
where C

is the asymptotic concentration of C as

z , and C
0
is the TB concentration at the tip of
a growing MT. We estimate the critical radius of an
ACC for which the gradient of concentration tends to
zero, i.e., V g =0, to nd
r
cr
=
_
3Vk
B
T
4
0
D(1

0
)
_
1/3
=0.4 m,
(6) d =0.8 m1 m.
At this size, the growth rate of an ACC equals the rate
of TB coagulation within a sweeping avalanche. Note
that this length scale corresponds to the smaller peri-
odicity (F) of MT bundles (Fig. 1(b)).
Importantly, the correlation length for this reaction
diffusiondrift effect, for P
e
=10
1
is
(7) l
cor
=
_
D(1 +P
e
)
K
cat
_
1/2
=3.3 mm,
where K
cat
is the rate of catastrophes taken to be 7
10
6
s
1
extrapolating from the estimate of Ref. [18]
and experimental results of Ref. [19]. While this value
is close to the observed periodicity (A) of 3 mm in
TEx (Fig. 1(b)), the situation would change drastically
if the conditions were close to the bifurcation point
(6 minutes after the onset of reaction), where K
cat
tends to zero and hence l
cor
diverges. Close to the bi-
furcation point this correlation effect becomes macro-
scopic giving rise to a globally self-organized state of
MT curtain domains (Fig. 1(a)). Thus both physi-
cal and chemical aspects of the process are needed in
order to create spatial and temporal self-organization
since they have comparable characteristic time scales.
The characteristic time for transport effects,
tr
,
is related to the spread of TBs along the z-direction
through the length L =

tr
D(1 +P
e
). Substituting

tr
=5 h together with D and P
e
used before one ob-
tains L = 1.2 mm, which compares reasonably well
with the width of one stripe (B) in TEx (Fig. 1(b)).
The chemical kinetics in TEx shows an over-shoot.
The MT assembly rate is at a maximum between 6 and
10 minutes after the onset of chemical instability af-
fecting the relative ratio of free TB and MTs. This co-
incides with the bifurcation time at which the systemis
gravity-dependent due to local massive depolymeriza-
tions and the formation of ACCs. At a later time, the
g-oriented MTs grow to be shorter (5 m on average).
Hence, further dynamical processes do not favor the
formation of isotropically oriented MTs. Highly ori-
ented MTs are on average separated by 0.3 m which
is beyond the Bjerrum length so that small repulsive
forces between MTs prevail. This is consistent with
liquid-crystal behavior of MTs within oriented cur-
tains. This also explains the reason why MTs do not
experience sedimentation effects in this phase of pat-
tern formation in TEx.
It has been conjectured in the literature that sin-
gle MTs possess ferroelectric and piezoelectric prop-
erties [1012]. This has been supported by molecu-
lar dynamics calculations [20] made possible by the
electron crystallography determination of the atomic-
resolution structure of TB. Recently, it was reported
[21] that a large negative charge ( 20e per TB
monomer) is distributed on the surface of MTs with
a clear asymmetry between the + and ends. A fur-
ther calculation of the permanent dipole moment per
TB dimer [22] (approximately 1.8 10
3
debye), indi-
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cated its orientation to be almost perpendicular to the
MT cylinder axis. This means that MTs are anisotropic
also with respect to their electric susceptibility. We as-
sume that
M

=4,
M

=2, for TEx conditions where

the concentration of TB is 10 mg ml
1
with 70% of
it being polymerized in MTs. Thus the relative vol-
ume ratio of MTs in solution is v = 0.007. It was
shown [7] that if the condition |v

| 1 holds, with

=

M

+
s
, the correlated thermal uctuations of
counterions along MTs ensure that the forces between
two oriented bundles of MTs become attractive. The
corresponding free energy density for two bundles
separated by the distance R, containing N MTs per
m
2
of area normal to the MTs axis has the form
F
vol
=N
2
k
B
T
64
A
2
_

3
2R
3
_

+
1
4

+

128
_
2cos
2
+1
_
_
(8) +

R
2
_

+
1
8

_
+R
4
ln(2R)
_
,
where A =
d
2
4
is the cross section of a MT, =
(
4n
2
c
e
2

s
k
B
T
)
1/2
is the inverse screening length with n
c
denoting the average concentration of the condensed
counterions along MTs. The MTs dielectric anisotropy
is highly important and expressed through

and
=

M

(
M

+
s
)3
M

s
(
M

+
s
)
. Finally, represents the angle
between the orientations of two neighboring bundles.
The free energy thus consists of three terms reecting
the monopolemonopole, dipoledipole and van der
Waals interactions, respectively.
Minimizing Eq. (8) with respect to the angle , we
obtain = /2 which agrees with the angle between
two halves of the curtain pattern (Fig. 1(a)). This
orientation is even more clearly expressed in the nal
striped pattern of TEx (Fig. 1(b)). It is evident that the
electrostatic interactions with counterion charge uc-
tuations lead to the result that MTs polymerized in the
gravitational eld during TEx form a polar liquid crys-
tal (LQ) phase [23]. Moreover, it is known [24] that
long cylinders generally tend to align parallel to each
other when their density exceeds a critical number

cr
L
2
d
1
. For MTs (L = 5 m and d = 25 nm),
this concentration is
MT
cr
1.5 10
18
m
3
. For the
concentration and length of MTs in TEx,
MT
TEx
= 3
10
18
m
3
>
MT
cr
, easily satises the conditions for
the onset of a LQ phase. Consequently, the LQ fea-
tures dominate in the pattern formation behavior after
the critical bifurcation state is reached under the action
of GF.
LQ properties of MTs affect their alignment with
the surface of the cell. For long MT cylinders (L d)
in TEx, condensing many MT ends at the surface car-
ries a high entropy cost and is therefore unlikely to
occur. This is consistent with the experimental fact
that MTs are aligned parallel to the cell wall corre-
sponding to the largest area 4010 mm
2
and pointing
toward the smallest surface area. Moreover, due to an
oblique alignment of MTs with the smaller surface ar-
eas ( = /4) a further reduction in the number of
MTs in contact is accomplished. Since the position of
a MT end with respect to the wall is determined up
to its diameter d, this signicantly reduces the cong-
urational entropy of one MT in contact by S
conf
=
k
B
ln(
L
d
) 5.3k
B
. This is why MTs in TEx are not
oriented vertically as expected fromgravitational ACC
effects. This orientation forms a close-packed layer of
MTs perpendicular to the surface and creates a new
surface a distance L into the bulk, at which location
the next layer of MTs must be properly arranged to
further reduce the entropy. Oblique orientations in-
duce splay effects especially near the corners of the
experimental cell where gaps between MTs open up,
into which other MTs can penetrate, restoring the ran-
dom distribution of MT ends. However, in the bulk,
the highly parallel oriented MTs still have to satisfy
the cooperative entropy condition.
The rotational relaxation of a single cylinder of
xed length is hindered by its disordered neighbors
when cylinder concentrations exceed

L
3
. With
L =5 m one obtains

=10
16
m
3
, which is much
more dilute than in TEx explaining why microgravity
conditions prevent pattern formation.
MTs that grow in a disorderly fashion are prevented
from establishing LQ order. If the system already pos-
sesses highly parallel ordering, as is the case of gravi-
tationally directed MTs within curtains, the entropy-
frustrated state should be relaxed by the spread of slow
rotational waves starting from the walls and lasting ap-
proximately 12 hours [4] or 5 hours [3,5] depending
on experimental conditions. These rotations are facil-
itated by the existing dynamical instability of MTs
but now are less dramatic than at the moment of the
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chemical instability (6 minutes after the onset of the
reaction).
Implications of the microgravity effects and their
explanation presented here extend to cell behavior as
was seen in another space ight experiment [25]. Fur-
thermore, it was recently reported [26] that in climbing
plants competing for light energy, MTs create a twist
obliquely oriented toward the cells long axis. This
suggests that symmetry breaking by the GF together
with structural changes within TB subunits related to
the rigidity of MTs, is the mechanism responsible for
pattern formation. Patterns in [26] clearly reveal the
LQ phase of MTs in vivo.
In conclusion, our theoretical model allows us to
make qualitative predictions regarding the emergence
of MT patterns on a function of several controllable
parameters such as the GF strength, pH, TB concen-
tration, and temperature. A comprehensive analysis of
the effect of these parameters will be published else-
where.
Acknowledgements
The authors thank NSERC, MITACS-MMPD and
the ITP at the University of Alberta for nancial
support. S. Portet has been supported by a Bhatia
post-doctoral fellowship. J.A. Tuszynski thanks Dr.
J. Tabony for his hospitality during his visit to Greno-
ble. Valuable discussions with Profs. A. Ramani of
Ecole Polytechnique Palaiseau and B. Grammaticos
of Universit Paris VII are gratefully acknowledged.
J.A. Tuszynski wishes to thank Dr. R. Binot for the in-
vitation to the microgravity workshop at the ESA at
Noordwijk, Holland.
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