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Nonlinear Analysis ( )
www.elsevier.com/locate/na
1
Nonlinear assembly kinetics and mechanical
properties of biopolymers 3
Jack Tuszy nski
a,,1
, Stphanie Portet
b,2
, John Dixon
c
a
Department of Physics, University of Alberta, Edmonton, Alberta, Canada T6G 2J1 5
b
The Samuel Lunenfeld Research Institute,Room 1060, Mount Sinai Hospital, 600 University Avenue,
Toronto, Ontario, Canada M5G 1X5 7
c
Department of Physics, University of Warwick, Coventry CV4 7AL, UK
Abstract
9
This paper discusses the role of nonlinearities in the physical description of key biomolecules that
participate in crucial subcellular processes, namely actin, microtubules and ions crowding around 11
these laments. The assembly kinetics of actin is that of a nonlinear process that is governed by
coupled nonlinear equations involving monomer concentration and lament number as the dynamical 13
variables. The dendritic growth of actin networks in cell motility phenomena is described by the
coupling of actin laments to the protein Arp2/3. We then discuss how coupled differential equations 15
describing the interactions between ions in solution and the lament they surround can lead to solitonic
signal transmission. We also investigate the role of nonlinear dynamics in the formation of micro- 17
tubules. Space-ight laboratory experiments have shown that the self-organization of microtubules
is sensitive to gravitational conditions. We propose a model of self-organization of microtubules in 19
a gravitational eld based on the dominant chemical kinetics. The pattern formation of microtubule
concentration is obtained in terms of a moving kink. Finally, we present a model of elastic proper- 21
ties of microtubules describing a microtubule as an elastic rod. We found that when the microtubule
is subjected to bending forces, the tangent angle satises a Sine-Gordon equation whose solutions 23

Corresponding author. Fax: +1 780 492 0714.

E-mail address: jtus@phys.ualberta.ca (J. Tuszy nski).
1
This work was supported by grants from MITACS and NSERC awarded to J.A.T.
2
S.P. acknowledges the support of the Bhatia post-doctoral fellowship.
0362-546X/$ - see front matter 2005 Published by Elsevier Ltd.
doi:10.1016/j.na.2005.01.089
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describe kink and anti-kink bending modes that may propagate at a range of velocities along the length 1
of the microtubule.
2005 Published by Elsevier Ltd. 3
Keywords: ; ;
1. Introduction 5
The cells cytoskeleton is composed of three different types of laments organized in
networks: microlaments (MFs), intermediate laments (IFs) and microtubules (MTs). 7
MFs are a double helix of globular actin subunits. In a lamellipod, the MF network appears
as a 3D gel which is involved in cell motility. The 2D arrangement of MFs in contractile 9
bers appears to formcable-like structures involved in the maintenance of the cell shape and
transduction pathways. The polymerization dynamics and lament organization of actin has 11
been modeled by Edelstein-Keshet et al. [6,9]. In the conguration of parallel strands, MFs
often formthe core of microvilli, while in an anti-parallel arrangement, actin in conjunction 13
with myosin brings about muscle contraction in the presence of ATP. MFs are often found
with the lattice conguration near the leading edge of growing or motile cells where they 15
provide greater stability to the newly formed region. New actin laments are nucleated at
the leading edge of the cells growth and trailing MFs are disassembled [2,3]. 17
MTs are long, hollow cylindrical objects made up of typically 13 longitudinal protola-
ments consisting of -tubulin heterodimers, and are involved in a number of functions of 19
the cell such as cell shape maintenance, mitosis and intracellular transport. By biological
standards, MTs are rigid polymers with a large persistence length of 6 mm. From Janmeys 21
experiments [14], MTs suffer a larger strain for a small stress compared to either MFs or
IFs. The rupture stress for MTs is very small and typically is about 0.40.5 N/m
2
[14]. The 23
ratio of exural rigidity per unit length to thermal energy in the case of MTs is of the order
of 100, whereas for actin it is only 2, meaning that the MTs are not greatly inuenced by 25
thermal agitation [30].
2. Actin laments 27
In this section, we give examples of the strong dependence of actins dynamic behaviors
on nonlinearities: two models of actin polymerization and one model of transport induced 29
by nonlinear properties of actin.
2.1. Polymerization dynamics of actin laments 31
Polymerization of F-actin from G-actin is a largely monotonic process that is dependent
onATP. F-actin assembles according to a standard nucleationelongation mechanism. Once 33
assembled, MFs have a diameter of about 8 nm. Oosawa and Asakura [22] established that
spontaneous polymerization of actin monomers requires an unfavorable nucleation step 35
followed by rapid elongation. They also determined that actin laments can break and anneal
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end to end. Inclusion of a fragmentation reaction improved the t of nucleationelongation 1
mechanisms to the observed time course of polymerization [4,7,29]. Earlier models for actin
polymerization showed that the critical size for the nucleus is somewhere between a dimer 3
and a trimer, and that the number of explicit nucleation steps does not affect the results of
the model [7,11,12,26]. With these considerations in mind, a simple ve-step model was 5
proposed [28]:
A + A
k
+1

k
1
A
2
k
+1
= 10 M
1
s
1
, k
1
= 10
6
s
1
, (1)
7
A + A
2
k
+2

k
2
A
3
k
+2
= 10 M
1
s
1
, k
2
= 10
3
s
1
, (2)
A + A
3
k
+3

k
3
A
4
k
+3
= 10 M
1
s
1
, k
3
= 10 s
1
, (3)
9
A + A
4
k
+4

k
4
N k
+4
= 10 M
1
s
1
, k
4
= 0 s
1
, (4)
A + N
k
+

N k
+
= 10 M
1
s
1
, k

= 1 s
1
, (5)
11
where A, A
i
, and N represent the concentrations of actin monomers, laments of i actin
monomers, and all longer laments, respectively. The rate constants for the last reaction 13
have been experimentally measured [23] and lead to the correct critical concentration
(C
c
>0.1 M), but the other rate constants are only approximations from kinetic simu- 15
lations, chosen to reproduce the time course of polymerization over a limited range of
actin monomer concentrations. Such polymerization curves have already been published 17
[4,7,11,12,26,29]. Filaments longer than 4 subunits are assumed to be stable and the back-
reaction rate k
4
is set to zero. The coupled rst-order differential equations that arise from 19
the set of reactions above are stiff-equations due to the large differences in the forward
and back reaction rates. This set of equations produces correct polymerization curves, but 21
the average length as a function of actin concentration is completely incorrect. The mean
lengths of the observed laments are almost independent of the initial concentration of actin 23
monomers, while this simple model predicts a mean length with quite a different behavior,
especially at high concentrations of actin. To solve this problem, additional processes are 25
added to the model, namely the reaction
N + N
k
a

k
f
N, (6)
27
where k
a
is the annealing rate and k
f
the fragmentation rate of a lament. Since two laments
are joined to form a new lament, the annealing rate has a quadratic dependence 29

N = k
+
AA
4
k
a
N
2
+ k
f
N. (7)
It is reasonable to assume that annealing of two laments is limited by diffusion, since 31
laments diffuse more slowly than monomers. Erickson [10] estimated the fragmentation
rate to be in the neighborhood of k
f
10
8
s
1
. 33
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The amount of polymerized protein in the system is given by the expression 1
P = A
0
A 2A
2
3A
3
4A
4
, (8)
where A
0
represents the initial actin concentration. The average length of a lament is given 3
simply by L = P/N and we get

N = k
+
AA
4
k

a
N
3
L
+ k

f
1
P + k

f
2
P
2
, (9)
5
where all of the constants are absorbed in the variable k

a
. The values for the rate constants
depend on the actin concentration and the lament density and length. 7
When actin is puried from cells some actin-associated proteins remain in the sample,
including the capping protein CapZ. A reaction for capping laments can be written as 9
CapZ + N
k
z+

k
z
N

, (10)
where N

represents a lament that is capped at the barbed end preventing monomer 11

addition or dissociation as well as annealing. The constants for the above reaction are
k
z+
3.5 M
1
s
1
and k
z
3 10
4
s
1
[25]. The total number of laments in the 13
system is N + N

and the average length is now given by

L =
P
N + N

. (11)
15
A capped lament can still fragment, but it can only anneal with an uncapped lament,
since this requires at least one free barbed end. Since two uncapped laments can anneal in 17
two ways, but capped and uncapped laments have only one method of annealing, the rate
of annealing is half the original value. 19
2.2. A simplied model for actin dendritic network aggregation
The nucleation of new F-actin laments is a prerequisite for cell shape remodeling and 21
motility processes involving rapid actin polymerization. It can either involve a de novo
nucleation of new laments or a catalytic nucleation from pre-existing laments. In the 23
de novo nucleation, a trimeric nucleation core initiates a new lament. New laments
resulting from a catalytic nucleation can be initiated either by the fragmentation of pre- 25
existing laments or by a branching process requiring the presence of the Arp2/3 protein
complex which is bound to the barbed end or to the side of a mother lament with the new 27
daughter lament polymerizing out from it at a 70

angle. The Arp2/3 complex has to be

associated with other molecules as WASP family proteins or cortactin to be active. During 29
these rapid actin polymerization processes, other important mechanisms take place, such
as the capping of the branched ends by, for example, gelsolin, avoiding polymerization 31
at these ends to not exhaust the G-actin pool and to promote polymerization at precisely
localized sites. All these processes induce strong nonlinearities. The events considered in 33
our simplied model follow.
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2.2.1. De novo nucleation 1
The nucleation core of F-actin is a trimer. This type of nucleation is G-actin dependent.
3G
v
+

F, (12)
3
where G is a G-actin monomer and F is a free F-actin lament.
2.2.2. Catalytic nucleation (branching) 5
The Arp2/3 complex is able to form new barbed ends by branching at the ends of existing
laments. WASP (and/or cortactin) is required for activation of the Arp2/3 complex: it 7
is a nucleation-promoting factor. This type of nucleation is F-actin dependent. Thus, the
catalytic nucleation involves different events. The rst step is the activation of the Arp2/3 9
complex,
W + A + G
:
Y, (13) 11
where W is a WASP molecule, A is an inactive Arp2/3 complex and Y is an active Arp2/3
complex. The second step of the catalytic nucleation is the branching process 13
F + Y
[
2F
N
+ W or F
N
+ Y
[
2F
N
+ W, (14)
where F
N
represents an F-actin lament involved in the dendritic network. 15
2.2.3. Polymerization/depolymerization
F + G

F or F
N
+ G

F
N
. (15)
17
These equations represent the elongation/disassembly processes of laments.
2.2.4. Debranching 19
F
N
o
F + A. (16)
The turnover betweenATP G-actin andADP G-actin is assumed to be instantaneous. The 21
sequestration of the soluble pool, the severing and the capping/uncapping of laments are
not considered in the model: all these processes involve the action of other types of proteins, 23
for example gelsolin. Thus, the proposed model could describe the self-aggregation of F-
actin laments into dendritic networks. The reversible processes of annealing/fragmentation 25
are not considered in our model.
We assume that the inactive Arp2/3 complex concentration, A, and the WASP protein 27
concentration, W, are constant. Thus, our model is composed of 4 state variables (G, Y, F,
and F
N
) and 7 parameters (v
+
, v

, :, [,
+
,

, and o). 29

G = 3v

F
. ,, .
Elimination
3v
+
G
3
. ,, .
Nucleation

+
G(F + F
N
)
. ,, .
Polymerization
+

(F + F
N
)
. ,, .
Depolymerization
:G
.,,.
Activation
, (17)

Y = :G
.,,.
Activation
[Y(F + F
N
)
. ,, .
Branching
, (18)
31
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0
1
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
G
F
F
N
0
1
0
0.1
0.2
0.3
0.4
0.8
0.6
0.4
0.8
0.6
0.4
0.2
0.2
0
0.05
0.1
0.15
0.2
G
F
F
N
Fig. 1. Insensitivity of the actin debranching process to the initial conditions and for various parameter choices
([ = 5, v
+
= 100 left; [ = 0.05, v
+
= 10 right).

F = v
+
G
3
. ,, .
Nucleation
v

F
.,,.
Elimination
+ oF
N
.,,.
Debranching
[FY
.,,.
Branching
, (19)
1

F
N
= 2[FY
. ,, .
Branching
+ [F
N
Y
. ,, .
Branching
oF
N
.,,.
Debranching
, (20)
where v
+
is the rate constant of lament nucleation by trimerization and v

is the rate 3
constant of nucleation core elimination. Here
+
and

represent the rate constants of

assembly of a G-actin monomer to an F-actin lament and of disassembly of a G-actin 5
monomer from an F-actin lament, respectively. Here : is the rate constant for the Arp2/3
complex activation by WASP proteins. [ is the rate constant of the lament branching, and 7
o is the rate of the dissociation of a lament from the network, the rate of debranching. All
the rate constants and the initial concentrations are positive. (See Fig. 1 for an illustration 9
of the dynamics of these equations.)
2.3. Actin laments as nonlinear ionic LRC transmission lines 11
In this section, we set up an electrical model of the actin lament using inductive, ca-
pacitive and resistive elements. We apply Kirchhoffs laws to that section of the effective 13
electrical circuit for one monomer, M, which involves coupling to neighboring monomers.
We expect a potential difference between one end of the monomer generated between the 15
lament core and the ions lying along the lament at one Bjerrum length away. Due to
viscosity we also anticipate a resistive component to these currents which we insert in se- 17
ries with L and denote it by R
1
. In parallel to these components, there exists a resistance,
R
2
, acting between the Bjerrum ions and the surface of the lament. In series with this 19
resistance, we have a capacitance, C
0
. We assume that the charge on this capacitor varies
in a nonlinear way with voltage. Thus for the nth monomer, 21
Q
n
= C
0
(V
n
bV
2
n
), (21)
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where b is expected to be small. From Kirchhoffs laws, 1
v
n
v
n+1
= L
dI
n
dt
+ I
n
R
1
, (22)
where v
n
and v
n+1
are the voltages across neighboring resistors. Similarly, if the voltage 3
across the capacitor is V
n
+ V
0
, where V
0
is the bias voltage of the capacitor,
v
n
= R
2
(I
n1
I
n
) + V
0
+ V
n
. (23) 5
Furthermore, the current difference is I
n1
I
n
= dQ
n
/dt . Combining and transforming
these equations, we obtain 7
L
d
2
Q
n
dt
2
= V
n+1
+ V
n1
2V
n
R
1
C
0
d
dt
(V
n
bV
2
n
)
R
2
C
0
_
2
d
dt
(V
n
bV
2
n
)
d
dt
(V
n+1
bV
2
n+1
)

d
dt
(V
n1
bV
2
n1
)
_
. (24)
A continuum approximation using a Taylor expansion in a small spatial parameter a 9
gives
LC
0
j
2
V
jt
2
= a
2
(j
xx
V)+R
2
C
0
j
jt
(a
2
(j
xx
V))R
1
C
0
jV
jt
+R
1
C
0
2bV
jV
jt
, (25)
11
which forms the basis of our physical analysis of the ion conduction problem [27].
As a result of applying an input voltage pulse with an amplitude of approximately 200 mV 13
anda durationof 800 s toanactinlament, electrical signals measuredat the opposite endof
the actin lament reached a peak value of approximately 13 nAand lasted for approximately 15
500 s [17]. In a related earlier experiment [18], the wave patterns observed in electrically
stimulated single actin laments were remarkably similar to recorded solitary waveforms 17
from various experimental studies on electrically stimulated nonlinear transmission lines
[16,19,21]. 19
Solutions of Eq. (25) are taken as traveling waves, so the voltage is a function of a
moving coordinate, = x v
0
t , where v
0
is the propagation velocity. Eq. (25) then 21
becomes
R
2
a
2
v
0
L
d
3
V
d
3
+ (v
2
0
c
2
0
a
2
)
d
2
V
d
2
+
_
2bR
1
v
0
L
V
R
1
v
0
L
_
dV
d
= 0, (26)
23
where c
2
0
= 1/(LC
0
). Eq. (26) may be integrated once to yield
R
2
a
2
v
0
L
d
2
V
d
2
+ (v
2
0
c
2
0
a
2
)
dV
d
+
1
2
_
2bR
1
v
0
L
V
R
1
v
0
L
_
2
L
2bR
1
v
0
= d
0
, (27)
25
where d
0
is an integration constant.
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To nd solutions in terms of Jacobi elliptic excitations, we choose the propagation ve- 1
locity, v
0
, so that v
2
0
= c
2
0
a
2
= v
2
max
. For convenience, we dene a shifted voltage by
W = V 1/(2b) and obtain an analytical solution in the form 3
W = w
3
(w
3
w
2
)sn
2
_
_
3a
2
R
2
(w
3
w
1
)
2

2bR
1
(
0
), k
_
, (28)
where 0k 1 with k =

(w
3
w
2
)/(w
3
w
1
) where k is the elliptic modulus. When 5
k 0 the sn() function tends to the trigonometric sine function. Simultaneously, the
amplitude of the wave vanishes and so does the wavelength. On the other hand, when 7
k 1 we obtain
W = w
1
+
2(w
2
w
1
)
1 + cosh(

w
2
w
1
(
0
))
. (29)
9
This solution represents a localized bump propagating with velocity v
0
. The waves in Eq.
(28) and the solitary wave in Eq. (29) travel at the velocity v
0
estimated as v
max
=310
5
m/s, 11
which is astonishingly high indicating a purely electromagnetic resonant energy transfer
from one LC element to the neighbor with no loss. 13
The voltage equation, Eq. (27), may be cast into the Fisher form by denoting dV/d as
V

, and rewriting it as V

+ zV

+ V
2
+ oV + c = 0 where 15
z=
(v
2
0
c
2
0
a
2
)L
R
2
a
2
v
0
, =
bR
1
a
2
R
2
, o=
R
1
R
2
a
2
, and c=
R
1
R
2
1
4ba
2

d
0
L
R
2
a
2
v
0
. (30)
We dene a change of variable V = :W + [, where : and [ are chosen as 17
: =

_
o
2
4c

and [ =
o +
_
o
2
4c
2
. (31)
Hence the traveling wave solution found is 19
V =
1
2b
+
_
d
0
L
bR
1
v
0
_

_
1 2
_
_
_
1 + p exp
_
_
_
q

_
2
a
2
R
2
_
bd
0
R
1
L
v
0

_
_
_
_

_
s
_

_
. (32)
The propagation velocity for the traveling kink solution is 21
v =
D(v
2
0
v
2
max
)L
R
2
a
2
v
0
. (33)
The velocity of ion ows in physiological situations, such as action-potential propagation 23
[1], ranges between 0.1 and 10 m/s; hence we estimate the corresponding nonlinear wave
velocities, v, to be 1 m/s v100 m/s. Actin interacts with a number of ion channels, of 25
different ionic permeability and conductance. Thus, it is expected that channel opening,
single-channel currents and other channel properties, including the resting potential of the 27
cell, may signicantly modify the amplitude and velocity of the soliton-supported waves.
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3. Microtubules 1
In this section, we give two examples of microtubule dynamics that are dominated by
nonlinearity. 3
3.1. MT polymerization in reduced gravitational elds
Space-ight laboratory experiments have shown that the in vitro and in vivo self- 5
organization of MTs is sensitive to gravitational conditions. In a previous work, we have
proposed a model of self-organization of MTs in a gravitational eld [24]. This reaction 7
diffusion model was based on the dominant chemical kinetics and on the interplay between
the diffusion processes and the drift induced by gravitational elds. We have considered as 9
chemical kinetics, the nucleation of laments and the elimination of the nucleation center,
the elongation and the shrinking of laments, the recycling of GDP-tubulin in GTP-tubulin. 11
It has been demonstrated that the polymerization of MTs proceeds in a traveling wave
fashion propagating with a constant velocity v. The tubulin concentration, C, as a function 13
of the moving coordinate, = x vt , describes a polymerization wave as follows:
C = 2
2/n
_
1 tanh
_
n
2

2n + 4
(
0
)
__
2/n
, (34)
15
where
0
is an arbitrary constant and n represents the number of dimers involved in the
nucleation center. The wave velocity v is dependent on n, v =(n+4)/(

2n + 4)

D
c
k
1
17
with D
c
the diffusion coefcient of tubulin dimers, and k
1
the recycling rate of GDP-tubulin
in GTP-tubulin. The nucleation process has been classically described as the power of the 19
GTP-tubulin concentration with nucleation exponents ranging from 6 to 12. This term
represented the strongest nonlinearity of the model. 21
3.2. The bending dynamics of MTs
In this section, we represent an MT as an elastic rod which can undergo large bending 23
motions. We rst dene the arc length, s, belonging to [0, L], where L is the MT length,
0(s, t ) is the tangent angle to the MT at position s and at time t . At time t , the curvature, 25
1/R
c
, of the MT at the position s is 1/R
c
=j0/js where R
c
is the radius of curvature. The
Lagrangian density can be expressed in terms of 0 as follows [5]: 27
L=
I
2L
_
j0
jt
_
2

f
2
_
j0
js
_
2
F cos 0
_
, (35)
where I is the moment of inertia and
f
is the exural rigidity [13]. The term(I/2L)(j0/jt )
2
29
represents the kinetic energy density, where j0/jt is the angular velocity. The second term,
(
f
/2)(j0/js)
2
, is the local elastic potential energy, and the third term, F cos 0 measures 31
the energy density expended in applying a force, F, to the MT. The moment of inertia, I, of
a rod, representing an MT, around an axis perpendicular to its length and passing through 33
one of its ends, is given by I = mL
2
/3, where m is the total mass of an MT of length L.
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The dynamics of the bending of an MT resulting from the EulerLagrange equation is 1
expressed by the nonlinear wave equation

I
L
j
2
0
jt
2
+
f
j
2
0
js
2
F sin 0 = 0 (36)
3
where the propagation velocity of the bending wave is v=

f
L/I. The change of variables,
x =
_
F

f
s and

t =
_
FL
I
t , rescales Eq. (36) to
5
j
2
0
jt
2

j
2
0
jx
2
= sin 0, (37)
where the tildes are omitted for simplicity. Eq. (37) has the form of the unperturbed Sine- 7
Gordon equation. It has one particularly important solution taking the formof a kink [15,20],
0(x, t ) = 4 tan
1
_
_
_
exp
_
_
_
(x vt x
0
)
_
1 (v/v
m
)
2
_
_
_
_
_
_
, (38)
9
where v
m
is the maximum phonon velocity. In addition, the Sine-Gordon equation [8] has
an innity of multi-soliton solutions T , but their physical signicance is unclear. 11
4. Summary and conclusions
Nonlinearities are very important in the physical description of several key biomolecules 13
that participate in a crucial subcellular processes, namely actin, MTs and motor proteins (es-
pecially kinesin). We showed in this paper that the assembly kinetics of actin is a nonlinear 15
process that requires not only a mechanism of saturation but also annealing and fragmen-
tation that are governed by coupled nonlinear equations involving monomer concentration 17
and lament number as the key variables. The observed dendritic growth of actin networks
in cell motility phenomena is subsequently described by the coupling of actin laments to 19
the protein calledArp2/3. Next, we discussed howcoupled differential equations describing
the interactions between ions in solution and ions on the lament can lead to solitonic signal 21
transmission.
We then discussed the role of nonlinear dynamics in the formation of MTs. First of all, 23
it has been known for more than a decade that high concentration of the constituent protein
tubulin leads to self-sustained oscillations in the assembly and disassembly dynamics of 25
MTs. We proposed a model of self-organization of MTs in a gravitational eld. The model
is based on the dominant chemical kinetics. The pattern formation of MT concentration is 27
obtained (1) in terms of a moving kink in the limit when the disassembly rate is negligible,
and (2) for the case of no free tubulin and only assembled MTs present [24]. The results of 29
our simulations are in good quantitative agreement with experimental data.
We presented a continuous medium model of the elastic properties of MTs that includes 31
large bending motions of MT laments by describing a MT as an elastic rod. We found
that when a MT is subjected to bending forces, the tangent angle satises a Sine-Gordon 33
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equation. Particular analytical solutions of this equation describe kink and anti-kink bending 1
modes that may propagate at a range of velocities along the length of the MT.
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