Force dependent transition rates in chemical kinetics models for motor proteins

Gianluca Lattanzi and Amos Maritan

Citation: The Journal of Chemical Physics 117, 10339 (2002); doi: 10.1063/1.1521422
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 JOURNAL OF CHEMICAL PHYSICS VOLUME 117, NUMBER 22 8 DECEMBER 2002

Force dependent transition rates in chemical kinetics models

for motor proteins
Gianluca Lattanzi
Hahn-Meitner Institut, Abt. Theoretische Physik SF5, Glienickerstrasse 100, 14109 Berlin, Germany
Amos Maritan
International School for Advanced Studies (S.I.S.S.A.) and INFM, Via Beirut 2-4, 34014 Trieste, Italy
and The Abdus Salam International Center for Theoretical Physics, Strada Costiera 11, 34100 Trieste, Italy
共Received 15 July 2002; accepted 20 September 2002兲
We analyze the role of external forces 共both chemical and mechanical兲 in the kinetics of motor
proteins. Based on a generalized detailed balance condition, simple exponential force dependent
transition rates are widely used to interpret the available data. Yet, the use of Fokker–Planck
equations in continuous models allows for a direct insertion of the force. We describe an analytical
approach, based on a renormalization group scheme, to calculate the force dependence of transition
rates in a generic model. Our analysis shows that the simple exponential is a good approximation to
the correct force dependence only at low values of forces and provided that the step sizes are very
small. The law for the force dependent transition rates is tested on a set of data on kinesin, obtaining
a good agreement with existing results and predictions for future experiments. © 2002 American
Institute of Physics. 关DOI: 10.1063/1.1521422兴

I. INTRODUCTION size. Furthermore they are more likely to be generalized, so

Experiments performed at the single molecule level are
revolutionizing our understanding of motor proteins, myo-
sins, kinesins, RNA polymerases, and many others. These
proteins are able to transduce the chemical energy of ATP
hydrolysis into mechanical work, that is used for many dif-
ferent purposes, ranging from muscle contraction to transport
of material in nerve cells. The results of these experiments
are often difficult to interpret, yet they constitute the best
that complicated chemical pathways can be investigated and
theoretical predictions can be compared directly to experi-
mental results 共see Kolomeisky and Fisher,3 and references
therein for examples兲. However the load dependence of tran-
sition rates in discrete models is still an open question. It is
generally believed that a tangential force F in the opposite
direction of motion of a diffusing particle would decrease its
forward transition rate, k ⫹ , for a step ␦, by the appropriate
Arrhenius factor,

source of information on the kinetic mechanism at the basis
of this important process. Stochastic models are particularly
suited to the interpretation of data that have been accumu-
lated in an impressive fashion in the last few years. In par-
ticular molecular force clamps have made it possible to exert
a constant force on motor proteins, and measure their veloci-
ties and diffusion constants under different loads, during
their normal cycle of operation. The effect of load on chemi-
cal kinetics is an intriguing open question in current biologi-
cal research and a fascinating field of interest for theorists in
statistical physics and probabilistic methods. Indeed continu-
ous models based on a system of coupled Fokker–Planck
共FP兲 equations1,2 provide a physically based answer to the
question of the effect of a force on the kinetics of motor
proteins and mechanochemical systems in general. Yet these
models are not directly suitable for the interpretation of ex-
perimental data, since the calculations involved are rather
cumbersome, the connection to the actual chemical cycle is
rather obscure, and, more importantly, they have been used
so far solely on infinitely periodic systems, while most of the
experiments are usually performed on a finite size scale.
On the other hand, chemical kinetics or discrete models
are more flexible, since they present the clear advantage of
rather simple calculations, a direct connection to the actual
chemical cycle and the applicability to systems of any finite
冉 冊
F␦
k ⫹ 共 F 兲 ⫽k ⫹ 共 0 兲 exp ⫺ . 共1兲
k BT
The same reasoning would yield an exponential increase
of the backward step with the same applied load. This in turn
leads to the prediction of exponential force dependence of
velocity, which is clearly unphysical. However a FP formu-
lation of the problem would imply a linear increase of veloc-
ity with force.
In this paper we develop an analytical approach, based
on a renormalization group scheme, to calculate the force
dependence of transition rates in discrete models. The ap-
proach is quite simple: In the limit of very small displace-
ments, discrete models must be equivalent to continuous
ones. This ‘‘continuum limit’’ has been already discussed.4
Once the transition rates have been established in the con-
tinuum limit, a renormalization group scheme is used to
eliminate a number of microscopic states of the system in a
self-consistent way. After renormalization, we are left with a
simple formula for the force dependence of transition rates in
chemical kinetics models. This formula is tested on a set of
data for the motor protein kinesin, leading to the interpreta-
tion of current results, predictions for future experiments and
hints on the kinetics of the energy transduction process.

0021-9606/2002/117(22)/10339/11/$19.00 10339 © 2002 American Institute of Physics

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 10340 J. Chem. Phys., Vol. 117, No. 22, 8 December 2002
II. THE GENERAL MODEL
We refer to the general picture proposed in a previous
paper.4 The system is described as a collection of states in a
periodic two-dimensional manifold in which one direction
represents the position of the center of mass along the linear
track 共the microtubule or the actin filament兲, whereas the
other is the reaction coordinate for the ATP hydrolysis.5 The
probability of being in a particular state-X at time t is written
as P X (t). The quantity W XY is defined as the transition prob-
ability per unit time from state Y to state X. It is assumed to
be time independent.
The time evolution of the system is simply given by the
master equation,
Ṗ X ⫽ 兺Y 共 W X,Y P Y ⫺W Y ,X P X 兲 .
Since the system is cyclic, transition rates are assumed to
be periodic,
W X⫹LN,Y ⫹LN ⫽W X,Y ,
where LN⬅(l 1 N 1 ,l 2 N 2 ), N 1 , N 2 are the periodicities in the
mechanical and chemical direction, respectively, and l 1 , l 2
are integers. For convenience, we have also introduced the
probabilities and transition rates summed over all periods,
following the formalism of Derrida,6
R X⬅ 兺L P X⫹LN ,
WX,Y ⬅ 兺L W X,Y ⫹LN .
The time evolution of R X is easily obtained from Eqs.
共2兲–共5兲,
Ṙ X ⫽ 兺Y ⬘共 WX,Y R Y ⫺WY ,X R X 兲 ,
where, by definition, a primed sum is restricted only to one
period along any axis.
The main advantage of this approach is its direct con-
nection to the continuous stochastic models, where the exter-
nal force term is easily inserted into the equations. As
pointed out in our previous work,4 a simple generalized de-
tailed balance condition 共GDB兲 is fully consistent with the
requirement that, in the continuum limit, a FP equation is
recovered. We therefore require that transition rates satisfy
the GDB,
WX,Y 共 F 兲 R̂ Y 共 0 兲 e F•Y ⫽WY ,X 共 F 兲 R̂ X 共 0 兲 e F•X ,
where R̂ X (0) is the 共unique兲 stationary equilibrium solution
of Eq. 共6兲 at F⫽0 and WX,Y (F) is the force dependent tran-
sition rate, still unknown.
It is important at this point to remark what we mean by
external force. In the GDB framework we use a generalized
force, defined as an externally tuned parameter able to drive
the system out of equilibrium. Any direction in the two-
dimensional manifold we are considering, entails a general-
ized force along that direction that is coupled, via GDB, to
the state variables along the same direction. For instance the
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G. Lattanzi and A. Maritan
mechanical force is coupled to the position of the motor
protein along the filament, while the chemical force, i.e., the
chemical potential difference in the hydrolysis reaction, is
coupled to the number of ATP molecules in solution.
We assume that transitions are possible only between
neighboring states, along both mechanical and chemical di-
rections. Of course, this is a simplification; more general
schemes with parallel branches and/or deaths can be found in
literature.3
For a more detailed analysis and a direct comparison
with experiments on kinesin, we refer to the simpler version
of the one-dimensional hopping models, already introduced.4
Such a simplification is appropriate for kinesin. Indeed the
mechanism for the energy transduction process has not been
resolved in motility assays: it may well be a power stroke
共2兲 mechanism or a rectified Brownian movement, or even a
combination of the two. As observed by Fox and Choi,7 both
mechanisms can be incorporated equally well into the gen-
eral continuous model proposed by Keller and Bustamante,5
共3兲 of which our model represents a discretized version.
We simplify the notation introducing a succession of N
states in one mechanochemical cycle and transition rates k ⫾i
in the positive 共negative兲 direction of motion from state i (i
⫹1) to state i⫹1 (i). We also assume that chemical energy,
expressed by the chemical potential difference ⌬ ␮ , is used
to overcome the first barrier in the transition from state 1 to
state 2 共see our previous work4 for a discussion on this
共4兲 point兲.
The next essential step is the choice of the potential of
mean force. Of course many choices are possible and, in the
共5兲 absence of exact calculations or direct measurements,
equally suited. We adopt the simplest potential, with the
minimum number of parameters, which allows for an opti-
mal fit of the available experimental data; it may reveal the
essential steps in the mechanism of energy transduction and,
共6兲 at least, can be invalidated easily by future experiments.
Although GDB is sufficient to recover the FP description
in the continuum limit,4 it is not enough to determine the
force dependence of mesoscopic transition rates, which are
currently used in discrete chemical kinetics models. A sen-
sible coarse graining procedure, described in the subsequent
sections, will allow us to determine this dependence starting
from a continuous formulation.
III. COARSE GRAINING PROCEDURE
We begin with the one-dimensional version of the model
described by Eq. 共6兲. The time evolution of R x , defined in
共7兲 Eq. 共4兲, is given by the following master equation:
Ṙ x ⫽Wx,x⫹1 R x⫹1 ⫹Wx,x⫺1 R x⫺1
⫺ 共 Wx⫹1,x ⫹Wx⫺1,x 兲 R x , 共8兲
where we are considering only a set of N discrete spatial
positions. The step performed by the motor in one transition
is given by ⌬x⫽1/N, where the period has been chosen as
the unit length. We introduce the Laplace transform,
R̃ x 共 s 兲 ⫽ 冕
0
⫹⬁
exp共 ⫺st 兲 R x 共 t 兲 . 共9兲
 J. Chem. Phys., Vol. 117, No. 22, 8 December 2002 Kinetics models for motor proteins 10341

The W dependence of R̃ x (s) is not indicated for simplic-
ity. The stationary condition is obtained in the limit t→⬁;
this limit is equivalent to the limit s→0 for the Laplace
transform. Applying this transformation to both sides of Eq.
共8兲, we find
共 s⫹Wx 兲 R̃ x ⫽R x 共 t⫽0 兲 ⫹Wx,x⫹1 R̃ x⫹1 ⫹Wx,x⫺1 R̃ x⫺1 ,
共10兲
where we have defined Wx ⫽Wx⫹1,x ⫹Wx⫺1,x . Since we are
where f is an applied external force, k B is the Boltzmann
constant, and T is the temperature. We assume the potential
of mean force not to be affected by the presence of an exter-
nal force, i.e., that the force is not able to alter the confor-
mation of the protein. Different potentials may account also
for the case of different protein conformations; nonetheless
we will restrict our study to the simplest case. Equation 共14兲
implies that the new transition rates satisfy the same Eq. 共17兲
with the new lattice spacing ⌬x ⬘ ,

冉 冊
interested only in the stationary solution, which is unique4,8
and reached independently of the initial condition, we as- ⬘
Wx⫹1,x ⫺V 关 2 共 x⫹1 兲兴 ⫹V 共 2x 兲 ⫹ f ⌬x ⬘
⫽exp . 共18兲
sume the initial condition to be R x (t⫽0)⫽ ␦ x,0 . ⬘
Wx,x⫹1 k BT
Now we introduce a decimation procedure over odd
sites:9 the idea is that the system properties should not de- Thus assuming that the GDB holds for the microscopic
pend on the particular choice of ⌬x. Therefore with our deci- transition rates, the GDB is preserved under the decimation
mation procedure we double the step ⌬x, and we ought to procedure, and hence, holds also for the mesoscopic transi-
obtain an evolution equation with the same form as Eq. 共10兲 tion rates, obtained after many iterations of the decimation
procedure. This simply means that the ratio of the forward
with new transition rates W⬘x ⬘ ,y ⬘ with x ⬘ ⫽x/2, y ⬘ ⫽y/2, and
and reverse rate constants gives the correct force depen-
⌬x ⬘ ⫽2⌬x. To this purpose, we just need to solve Eq. 共10兲
dence, as already reported,10,11 even though the single rate
for R̃ 2x⫹1 ,
constants are not Arrhenius-type. This property enforces our
W2x⫹1,2共 x⫹1 兲 W2x⫹1,2x confidence in the coarse graining procedure.
R̃ 2x⫹1 ⫽ R̃ 2 共 x⫹1 兲 ⫹ R̃ 2x . 共11兲
s⫹W2x⫹1 s⫹W2x⫹1 IV. APPLICATION TO LINEAR POTENTIALS
Writing the same equation for R̃ 2x⫺1 and substituting We apply the coarse graining procedure to a potential
these expressions in the equation for R̃ 2x , we finally obtain which is linear in an interval 关 0,L 兴 ; this example is of great
R̃ ⬘x 共 s ⬘ ⫹Wx⬘ 兲 ⫽ ␦ x,0⫹Wx,x⫹1
⬘ ⬘ ⫹Wx,x⫺1
R̃ x⫹1 ⬘ ⬘ ,
R̃ x⫺1 共12兲 importance for two reasons: first, any potential shape can be
always approximated by a piecewise linear potential, second
where an eventual external force may be also described as a tilt in
the potential shape, and therefore by a linear potential.
R̃ x⬘ 共 s ⬘ 兲 ⫽A ⫺1 R̃ 2x 共 s 兲 , 共13兲
We therefore assume V(x) to be linear in x (dV/dx
W2x,2x⫾1 W2x⫾1,2共 x⫾1 兲 ⫽const), and we define
⬘
Wx,x⫾1 ⫽A , 共14兲
s⫹W2x⫾1 1 dV f
⫹ 共19兲

冋 册
F⫽⫺ .
W2x⫹ ⑀ ,2x k B T dx k B T
s ⬘ ⫽As 1⫹ 兺
⑀ ⫽⫾1 s⫹W2x⫹ ⑀
. 共15兲 We now write

The amplitude A in the above equations is, at the mo- W⫹ ⫽Wx⫹1,x ⫽e F ⫹ , 共20兲
ment, arbitrary and it can be fixed appropriately depending W⫺ ⫽Wx,x⫹1 ⫽e F ⫺ , 共21兲
on the purposes. In what follows, we choose it to be inde-
pendent of the iteration step 共other instances are possible9兲. F ⫹ ⫺F ⫺ ⫽F⌬x. 共22兲
Since R̃ ⬘x (s ⬘ ) is the solution to Eq. 共12兲, which has the same The last equations ensure the GDB for microscopic tran-
form as Eq. 共10兲, the functional dependence of R̃ x⬘ on s ⬘ and sition rates. We apply now the coarse graining procedure and
W⬘ is the same as that of R̃ x on s and W; therefore we can obtain in the s→0 limit,
safely omit the prime and use R̃ x (s ⬘ ) in subsequent calcula-
tions. AW⫹
⬘⫽
W⫹ , 共23兲
In the large time limit, e.g., in the s→0 limit, Eq. 共15兲 1⫹r
simplifies and becomes

冉 冊
ArW⫺
W2x⫹ ⑀ ,2x ⬘⫽
W⫺ , 共24兲
s ⬘ ⫽As 1⫹ 兺
⑀ ⫽⫾1 W2x⫹ ⑀
⫹o 关 s 2 兴 . 共16兲 1⫹r
with r⫽W⫺ /W⫹ ⫽e ⫺F⌬x . Also r is transformed in the
Now, let us assume that the generalized detailed balance, coarse graining procedure, so that r ⬘ ⫽r 2 . We iterate this
Eq. 共7兲, holds for the transition rates W’s; since R̃ x (0) procedure for n steps,
⬀exp(⫺ ␤ V(x)), where V(x) is the 共periodic兲 potential of n
mean force, we obtain r 共 n 兲 ⫽r 2 , 共25兲

Wx⫹1,x
Wx,x⫹1
⫽exp 冉 ⫺V 共 x⫹1 兲 ⫹V 共 x 兲 ⫹ f ⌬x
k BT
冊 , 共17兲 W共⫹n 兲 ⫽
兿 k⫽0
n⫺1
A n W⫹
共 1⫹r 共 k 兲 兲
, 共26兲

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 10342 J. Chem. Phys., Vol. 117, No. 22, 8 December 2002 G. Lattanzi and A. Maritan

where n is such that

L⫽⌬x 共 n 兲 ⫽2 n ⌬x. 共27兲
2 n ⫺1 l
It is simple to show that 兿 k⫽0
n⫺1
(1⫹r (k) )⫽ 兺 l⫽0 r
n
⫽(r 2 ⫺1)/(r⫺1), so that
W⫹ 共 L,F 兲 ⬅W共⫹n 兲

⫽ 冉 冊
L
⌬x
共 ln A/ln 2兲
F⌬x
1⫺exp共 ⫺FL 兲
W⫹ 共 ⌬x 兲 ,

in the small ⌬x limit. We assume that in this limit, the tran-
sition probability W⫹ ⬅W⫹ (⌬x) does not depend on the de-
tailed potential shape.28 As already shown,4 the FP equation
is recovered in the continuum limit, when
D
W⫹ ⫽ , 共29兲
⌬x 2
where D is the local diffusion coefficient. Substituting Eq.
共29兲 in Eq. 共28兲, we obtain
F⌬x ⫺ 共 1⫹ln2 A 兲
W⫹ 共 L,F 兲 ⫽DL ln2 A . 共30兲
1⫺exp共 ⫺FL 兲
If we require that W⫹ does not depend on the particular
choice of ⌬x, the parameter A should take the value 1/2.
With this substitution, we finally obtain our force dependent
transition rates,
F exp共 ⫾FL/2兲
W⫾ 共 L,F 兲 ⫽D . 共31兲
2L sinh共 FL/2兲
With this choice we get also s ⬘ ⫽s⫹O(s 2 ) from Eq.
共15兲. Equation 共31兲 has been obtained under the following
hypotheses:
共i兲 The motion of the protein from one site to the other is
the result of Brownian diffusion in a linear potential.
共ii兲 A discrete chemical kinetics model with few states is
apt to describe this motion.
共iii兲 The continuous FP description is recovered when the
steps taken by the motor protein are small.
These hypotheses are rather general and could hence be
supposed to hold for a wide class of motor proteins and
biological systems.
V. FORCE DEPENDENT TRANSITION RATES
We have applied our coarse graining to a linear potential.
A more general potential of mean force can be approximated
by a piecewise linear potential as shown in Fig. 1. Our for-
mula can be applied to each of the linear pieces, and there-
fore a discrete model is generated.29 For a potential barrier
U, our model would predict force dependent forward/
backward rates of the form,
D f L⫺U e ⫾ 共 f L⫺U 兲 / 共 2k B T 兲
W⫾ ⫽
k BT 2L 2 sinh关共 f L⫺U 兲 /2k B T 兴
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共28兲
FIG. 1. Approximation of a generic potential of mean force with a piece-
wise linear potential, for which our coarse graining procedure can be per-
formed, leading to a 4 states model. Units are arbitrary.
In motility assays, measurable quantities are usually
given in terms of the load applied to the motor proteins,
which is simply a negative force in our model, ⫺ f .
A nice feature of Eq. 共31兲 is that no extra parameters are
introduced to account for a difference between forward and
backward transition rates. As remarked by Astumian and
Bier,12 there is a priori no reason why we should use differ-
ent apportionment of forces between forward and backward
transition rates.
Our approach shows that a different apportionment of
force in a coarse grained model may arise even from an
unbiased microscopic mechanism, without invoking different
exponential prefactors. This, in turn, reduces the total num-
ber of parameters needed to fit the experimental data.
A similar approach based on numerical integrations of a
piecewise linear potential was used by Keller and
Bustamante,5 to derive force dependent transition rates. De-
tailed calculations indeed showed different behaviors in the
forward and backward transitions. The same model predicted
forward 共backward兲 transition rates linear in force at large
positive 共negative兲 loads. This is clearly in contrast with
models with pure exponential 共or Arrhenius兲 load depen-
dence. As observed,5 this should be taken into account when
fitting the experimental data with a pure exponential law, of
the Arrhenius form, since a fit of the rate constants to an
exponential function would lead eventually to different val-
ues of the evaluated activation free energy from one range of
forces to the other.
It is striking to observe that our model, based on a dif-
ferent approach, leads essentially to the same behavior,5 with
forward 共backward兲 rate constants linear at large negative
共positive兲 loads 共see Fig. 2兲 and almost exponential at small
forces. Furthermore, models with pure exponential load de-
pendence would indeed predict positive exponential veloci-
ties for high forces and negative exponential velocities for
high loads, which is clearly unphysical. In our case the force
dependence is at most linear with high positive 共or negative兲
forces.
Non-Arrhenius force dependence of the very same form
proposed in Eq. 共31兲 has been already reported for the total
velocity of a motor protein,13 simply assuming the GDB and
. 共32兲
a velocity linear with force at low loads.
 J. Chem. Phys., Vol. 117, No. 22, 8 December 2002
M T, 共33兲
FIG. 2. Forward–backward transition probability vs load. Free energy dif-
ference U/k B T⫽5, T⫽300 K, L⫽4 nm, and D⫽0.1 ␮m2/s.
The Arrhenius form is a good approximation only if all
mechanical substeps taken by the motor protein along the
linear track are very small 关a reasonable choice of parameters
in Eq. 共31兲 would indicate 1 nm substeps and 1 pN forces兴.
Therefore, the purely exponential load dependence is a good
approximation for chemical steps which are thought to occur
M 2 T
M 3 T, 共34兲
without a net advancement of the motor protein,14 but not for
all substeps and not for the whole range of forces studied in
motility assays.
VI. MINIMAL MODELS
The general classification introduced by Keller and
Bustamante5 can be transferred to our model, with a great
simplification of the calculations and the number of param-
eters used. There are essentially 2N⫹1 parameters: the size
of individual steps (N), the potential differences between
successive positions (N) and an overall multiplicative factor
related to the macroscopic diffusion coefficient. Two other
parameters may be conveniently used to describe the chem-
istry of the reaction, i.e., the dependence of rate constants on
ATP concentration, and on reaction products. The total num-
ber of parameters is therefore 2N⫹3. Yet, two conditions
reduce the number of parameters: the sum of individual steps
is equal to one period, and the sum of potential differences
M 2 T
M 3 T
M 4 T
M 1 ⫹D; 共35兲
must yield zero since the system is periodic. The total is
2N⫹1, to be compared with the 4N⫺1 parameters of mod-
els with Arrhenius dependence and different force apportion-
ments.
Our approach is therefore suited to generate a class of
minimal models, for which few parameters are needed. How-
ever experimental results may suggest to enrich these mini-
mal models with branch or death processes, or waiting time
distributions, for which detailed calculations have been re-
M 2 T
M 3 T
M 4 ⫹D
M 1 . 共36兲
cently performed.3
Our coarse graining procedure has been shown to be
consistent with the FP equation approach, in the continuum
limit, with a simplification of the mathematics involved. The
obtained reaction rates depend only on the general shape of
the potential, and not on its full details. The results above
apply only to first-order processes, but GDB accounts also
for second order processes. The reaction rate should be mul-
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Kinetics models for motor proteins 10343
tiplied by the concentration of the chemical species involved
and a new parameter is introduced. The discussion reported
by Keller and Bustamante5 applies exactly to our model: if
we introduce a second order step to describe the mecha-
nochemical binding of ATP (T) to the motor protein (M ),
k 1共 f 兲
M ⫹T
k ⫺1 共 f 兲
where MT represents the bound state of the motor protein,
the force dependence of reaction rates k 1 ( f ), k ⫺1 ( f ) implies
that the binding step involves net motion. Indeed, as con-
firmed by experimental results,14 and already observed,15 the
spatial step covered by the motor upon binding, should be
very small. Keller and Bustamante5 point out that every
binding process should involve at least two parts: a purely
second-order process in which two molecules come into
loose contact by diffusion alone, and a first order process in
which the two molecules undergo conformational changes
that result in a more strongly bound state. It is therefore
possible to divide the single step above into an equivalent
two-step process,
k1 k 2共 f 兲
M 1 ⫹T
k ⫺1 k ⫺2 共 f 兲
where M 1 , M 2 , M 3 represent different states of the motor
protein. The rate constants for the first step are assumed to be
independent of force. This assumption means that the exter-
nal force acts on the protein, but not on the fuel molecule
directly, so that the purely diffusive part of the binding is
force independent. In a minimal model, we may assume that
a third step corresponding to ADP (D) dissociation, closes
the cycle, so that the motor is finally in its initial state M 1
and a new ATP molecule can bind. Furthermore we assume
this step to be described by two transitions: a first-order one,
corresponding to conformational changes and a second one
accounting for release of products. Two choices are possible:
共a兲 the conformational change is followed by the release of
products,
k1 k 2共 f 兲 k 3共 f 兲 k4
M 1 ⫹T
k ⫺1 k ⫺2 共 f 兲 k ⫺3 共 f 兲 k ⫺4
共b兲 the conformational change follows the release of prod-
ucts. In line with the previous reasoning, we assume the con-
formational change to be force-dependent and the release of
products to correspond to a negligible advancement of the
motor,
k1 k 2共 f 兲 k3 k 4共 f 兲
M 1 ⫹T
k ⫺1 k ⫺2 共 f 兲 k ⫺3 k ⫺4 共 f 兲
We observe that these models are more detailed than
those proposed by Keller and Bustamante.5 At least two tran-
sition rates are force dependent. The detailed mechanochemi-
cal picture can be different and more complicated. We de-
cided to use these models since they represent a simple, yet
general picture, consistent with the schemes proposed in the
 10344 J. Chem. Phys., Vol. 117, No. 22, 8 December 2002
FIG. 3. Simplified 4 state model for kinesin. ATP binding is used to over-
come the potential barrier U 1 and it is followed by a diffusive step of
approximately 4 nm. A second barrier is overcome before product (D) re-
lease with a second diffusive step of 4 nm.
recent literature.14,16 –18 The steps corresponding to ATP
binding and ADP dissociation are assumed to be purely dif-
fusive, i.e., they are negligibly small in the range of force
studied 共⫺6 pN, 6 pN兲. This approximation is valid as long
as f LⰆU.
For other models in the same spirit, and for a compari-
son with experiments, the interested reader could refer to
Mogilner et al.,18 where a formula with close resemblance to
Eq. 共31兲 is derived from simple arguments for the force de-
pendence of some transition rates.
VII. CHOICE OF POTENTIAL
The advances in the field of single molecule manipula-
tion for kinesin have permitted to measure the velocity under
an externally applied load at a given ATP concentration. At
the same time it is possible to measure the randomness pa-
rameter, which is directly related to the macroscopic diffu-
sion constant. In our previous work,4 we showed how to
calculate the velocity for any discrete model, whereas the
macroscopic diffusion constant was calculated only for
simple 2- and 3-state models. We sketch in the Appendix
how to calculate the diffusion constant in any discrete model,
with the formalism already introduced, using the method
proposed by Koza.19,20
We now need to give an estimate for all the parameters
of the model, in particular for the potentials. For model 共a兲
we assume the simple potential depicted in Fig. 3. The
chemical energy of ATP binding is used to overcome the first
barrier in the potential U 1 , then energy is released, when the
motor head diffuses in the positive direction, so that a sub-
step of ⬃4 nm is performed. The reason for choosing sub-
steps of this size resides in the experiments reported by the
Yanagida’s lab.17
As assumed above, the product release does not corre-
spond to any net advancement of the motor protein, and it is
only driven by a difference in chemical potential, so that a
M 3 T and M 4
M 1 in our case,
second minimum in the potential may arise. Although the
kinetic mechanism leading to this potential is rather obscure,
our picture is that ATP triggers a conformational change
which is responsible for the likelihood of the center of mass
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G. Lattanzi and A. Maritan
FIG. 4. Simplified 4 state model for kinesin. ATP binding is used to over-
come the first potential barrier and it is followed by a diffusive step of
approximately 4 nm and a drop in the potential of height U 1 . A small
second barrier is overcome during product (D) release, which triggers a
second diffusive step of 4 nm.
to move towards the plus end of the microtubule, sliding
down the first hill in the potential. Then a new conforma-
tional change triggers the release of reaction products and the
attachment to the next microtubule binding site. The reduced
potential difference for the second barrier accounts for the
difficulty to undergo this conformational change.
Using this model we were not able to fit the data.21 It is
indeed possible to show that the Michaelis constant for such
a model depends linearly on the maximum attained velocity,
therefore it decreases with load as long as the maximum
attained velocity does so.
We therefore switch to model 共b兲. The potential for this
model is represented in Fig. 4. In this case we assume that
the product release takes place when the protein is in a local
minimum at a distance of 4 nm from both microtubule bind-
ing sites. The release of products leads to a second confor-
mational change which finally leaves the protein in its initial
state. We will show here only results for this simplified
4-state mechanochemical reaction model 共b兲, Eq. 共36兲.
The master equation is given by the following system of
equations:5
Ṙ 1 ⫽⫺ 共 k ⫺4 ⫹k 1 关 T 兴 兲 R 1 ⫹k ⫺1 R 2 ⫹k 4 R 4 ,
Ṙ 2 ⫽k 1 关 T 兴 R 1 ⫺ 共 k ⫺1 ⫹k 2 兲 R 2 ⫹k ⫺2 R 3 ,
Ṙ 3 ⫽k 2 R 2 ⫺ 共 k ⫺2 ⫹k 3 兲 R 3 ⫹k ⫺3 关 D 兴 R 4 , 共37兲
Ṙ 4 ⫽k ⫺4 R 1 ⫹k 3 R 3 ⫺ 共 k ⫺3 关 D 兴 ⫹k 4 兲 R 4 ,
where 关 T 兴 and 关 D 兴 represent the ATP and product 共ADP and
P i ) concentrations in the two second-order steps involved.
The stationary solution to Eq. 共37兲 allows us to compute all
quantities of interest, as shown for a general class of discrete
models.4,5 The velocity is simply given by the filament peri-
odicity, p⫽8 nm in the case of kinesin, times the next flux in
the diffusive steps, M 2 T
a 关 T 兴 ⫺b 关 D 兴
v⫽p , 共38兲
e 关 T 兴 ⫹ f 关 T 兴关 D 兴 ⫹g 关 D 兴 ⫹h
with
 J. Chem. Phys., Vol. 117, No. 22, 8 December 2002 Kinetics models for motor proteins 10345

TABLE I. Transition rates for the 4 states model described by Eq. 共36兲. The force, f, must be expressed in pN,
the ATP concentration, 关 T 兴 , in ␮M. The model corresponds to two substeps, each of size 4 nm; the potential
constants appearing in Fig. 4 are U 2 ⫽12 k B T and U 4 ⫽4 k B T at room temperature, T⫽298 K.

k1 3 ␮M⫺1 s⫺1 k ⫺1 3000 s⫺1

共 6⫹0.48• f 兲 •e 6⫹0.48• f
共 6⫹0.48• f 兲 •e ⫺6⫺0.48• f
k2 200 s⫺1 k ⫺2 200 s⫺1
sinh共 6⫹0.48• f 兲 sinh共 6⫹0.48• f 兲

k3 140 s⫺1 k ⫺3 undetermined

共 2⫹0.48• f 兲 •e 2⫹0.48• f 共 2⫹0.48• f 兲 •e ⫺2⫺0.48• f

k4 200 s⫺1 k ⫺4 200 s⫺1
sinh共 2⫹0.48• f 兲 sinh共 2⫹0.48• f 兲

a⫽k 1 k 2 k 3 k 4 , 关ATP兴 at small concentrations, while it saturates at v max for

high concentrations. The quality of these fits can be judged
b⫽k ⫺1 k ⫺2 k ⫺3 k ⫺4 , from a direct comparison with experimental data.21 Our
e⫽k 1 共 k 2 k 3 ⫹k ⫺2 k 4 ⫹k 2 k 4 ⫹k 3 k 4 兲 , model predicts a drop in velocity at about 6 –7 pN, the same
stall load observed in experiments. It is interesting to observe
f ⫽k 1 k ⫺3 共 k 2 ⫹k ⫺2 兲 , that our model predicts an exponential drop of velocity and
g⫽k ⫺3 共 k ⫺2 k ⫺4 ⫹k ⫺1 k ⫺4 ⫹k ⫺1 k ⫺2 ⫹k 2 k ⫺4 兲 , not an inversion of the direction of motion. The stall load can
be calculated, assuming that experimental devices are not
h⫽ 共 k ⫺1 k ⫺2 ⫹k ⫺1 k 3 ⫹k 2 k 3 兲共 k 4 ⫹k ⫺4 兲 . able to detect velocities below a certain cutoff 共dictated by
In the limit of small product concentrations 关 ADP兴 experimental precision兲. It is however important to notice
关 P i 兴 , transitions from state 3 to state 4 共ADP release兲 are
that this model does not predict an inversion of velocity; to
irreversible and the model is further simplified: the velocity our knowledge, no motor protein has been observed to re-
follows Michaelis–Menten kinetics, verse its velocity even under high forces: backward steps are
possible, but the sign of velocity is always the same. This is
v max关 T 兴 an important and strong prediction of our model.
v⫽ , 共39兲 In Fig. 6, we plot the velocity versus ATP concentra-
关 T 兴 ⫹K M
tions, at different loads. We observe that the velocity follows
where v max is the maximum attained velocity at high 关 T 兴 , the Michaelis Law, at all concentrations and all values of
force. We have already reported that the Michaelis Law
a k 2k 3k 4
v max⫽p ⫽ p , 共40兲 should be modified to account for the possibility of steps in
e k 2 k 3 ⫹k ⫺2 k 4 ⫹k 2 k 4 ⫹k 3 k 4 the negative direction of motion.15 Our results from the dis-
and K M is the Michaelis constant, crete model seem to be in contrast with those findings; in-
deed our discrete models do not allow backward cycles to be
h 共 k ⫺1 k ⫺2 ⫹k ⫺1 k 3 ⫹k 2 k 3 兲共 k 4 ⫹k ⫺4 兲 completed, since we assumed that the concentration of the
KM⫽ ⫽ . 共41兲
e k 1 共 k 2 k 3 ⫹k ⫺2 k 4 ⫹k 2 k 4 ⫹k 3 k 4 兲 reaction products is 0. In real experiments, this concentration
is assumed to be negligible, but it is not zero; if backward
Since some of the transition rates are force dependent, cycles are possible, a correction to the Michaelis Law in the
the Michaelis constant is force dependent, as experimentally
observed.

VIII. COMPARISON WITH EXPERIMENTAL RESULTS

The choice of parameters is a difficult problem, since no
information on the detailed mechanism is available. We de-
cided to use the reaction rates reported by Moyer et al.22 as
starting values, and then varied these parameters so as to fit
the data from Block’s lab.21,23 The number of parameters is 3
for the chemical steps (M 1 ⫹T
M 2 T and M 3 T
M 4
⫹D), and 5 for the force dependent ones 共the two step sizes,
the two potential differences and the multiplicative factor
which depends on the step size and therefore is the same for
both mechanical steps兲. All transition rates obtained by the
fit, are reported in Table I.
FIG. 5. Load-velocity curves for different ATP concentrations. Top to bot-
In Fig. 5, we plot the velocity attained by the motor tom curves: 关 T 兴 ⫽2 mM, 1 mM, 100 ␮M, and 5 ␮M. Filled circles refer to
protein under different loads, for different ATP concentra- experimental data from Visscher et al. 共Ref. 21兲 at 关 T 兴 ⫽2 mM and 5 ␮M.
tions. The zero load velocity is approximately linear with The size of the data points represents the experimental error.
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 10346 J. Chem. Phys., Vol. 117, No. 22, 8 December 2002
FIG. 6. Michaelis–Menten kinetics under load. Double logarithmic plot of
the average bead velocity, vs ATP concentration for various loads (⫺ f ).
Experimental data are shown with different point types.
form already proposed, appears also in the model.
Remarkably, our model allows for a direct calculation of
the Michaelis constant, K M , which is expressed by Eq. 共41兲.
K M depends on force and is plotted in Fig. 7; it increases
with load, as observed.21 The model not only agrees, quali-
tatively and quantitatively, with experimental results, but it
also allows us to calculate K M in the region of negative
loads. In particular we find that K M should show a much less
pronounced variation with negative loads and should slowly
decrease with force.
In our opinion, it is crucial to compare these results with
experiments. To our knowledge, only an increase in the
Michaelis constant in the region of positive loads has been
observed so far. The region of positive force has been
investigated,24 but the Michaelis constant and its variation
with force have not been measured yet. Therefore, new ex-
periments aimed at investigating this parameter region, al-
though difficult, are extremely important to confirm or reject
our predictions.
The macroscopic diffusion coefficient is defined as the
long time limit of the ratio between the variance of the pro-
tein position along the filament, 具 x 2 (t) 典 ⫺ 具 x(t) 典 2 , and time t,
FIG. 7. Michaelis constant at different loads. The predicted behavior is in
agreement with experimental data 共filled circles in the figure兲: the Michaelis
constant increases with applied load.
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G. Lattanzi and A. Maritan
FIG. 8. Randomness parameter vs ATP concentrations at different 共positive
and negative兲 loads. The curve at 0 load is shown as a solid line, for refer-
ence.
具 x 2共 t 兲 典 ⫺ 具 x 共 t 兲 典 2
D⫽ lim . 共42兲
t→⬁ 2t
Full details of the calculations needed to estimate the
macroscopic diffusion coefficient are given in the Appendix.
The method is applied to a 4 state model, but it can be
generalized to models with any number of states using the
method introduced by Koza.19,20 Here we present the results
in terms of randomness, a dimensionless parameter,25 which
is related to the diffusion coefficient,
2D
r⫽ , 共43兲
pv
where p is the filament periodicity and v is the motor veloc-
ity. In the case of motor proteins, this parameter is more
appropriate, since its reciprocal represents the number of rate
limiting steps. See Wang et al.26 for a discussion on this
point.
We plot in Fig. 8 the randomness parameter as a function
of ATP concentration at different loads. Its variability with
load is not trivial at all; indeed the agreement with the ex-
perimental data is only of a qualitative nature. We observe
that our model predicts a randomness parameter always
smaller than 1. This is in contrast with experiments, where
randomness parameters ⬎1 have been measured.21 As
pointed out in the same reference, the increase in r above
unity probably reflects the occurrence of 8-nm backward
steps. In our model, these backward steps are not allowed by
the choice of an irreversible reaction rate k 3 due to the lack
of reaction products. If the cycle is allowed to be reversible,
keeping a finite k ⫺3 and a not negligible product concentra-
tion, the randomness does increase above unity in some re-
gions of the parameter space, and remarkably in those re-
gions where the velocity is close to zero 共typically at low
ATP concentrations and large forces兲. Indeed, backward
steps are observed with a higher probability under high
loads,17 hence they are likely to raise the observed random-
ness factor above our predicted value 0.5. Following these
considerations, our predictions should be used only as esti-
 J. Chem. Phys., Vol. 117, No. 22, 8 December 2002
FIG. 9. Randomness factor measured for various loads at different ATP
concentrations.
mates on the minimum values for the randomness parameter
observed in real experiments. The randomness parameter is
smaller than 1/2, indicating that more than two steps are
rate-limiting at low loads and low ATP concentrations. At
high ATP concentrations and low loads, there are essentially
two rate-limiting steps. Therefore the first step is rate limit-
ing at low ATP concentrations, while at high ATP concentra-
tions, the third and fourth steps are rate limiting. Transition
rates for these steps are not numerically equivalent, hence the
predicted randomness factor ⬎1/2. At high loads and high
ATP concentrations, there are essentially two rate-limiting
steps, the third and fourth ones and they are almost equiva-
lent, r⫽1/2.
We remark that the same crossing of curves has been
observed in experiments21 and that our results were obtained
by a simple fit to a small set of data for the maximum at-
tained velocity. In Fig. 8, we also plot the randomness in the
region of negative loads. Again results in this parameter re-
gion, to our knowledge, are not yet available.
In Fig. 9 we plot the randomness parameter as a function
of the applied force at different ATP concentrations. Mea-
surements at high loads are extremely difficult, since the mo-
tor is likely to detach from the microtubule,30 as observed.21
An inspection of Fig. 9 reveals that at low ATP concentra-
tions, there are essentially 2 rate-limiting steps, the first one
and the fourth one which becomes the only rate-limiting step
at high loads. At higher ATP concentrations, only one step is
rate limiting, the force dependent one, as revealed by the 100
␮M curve. Indeed at low loads, the first step is still rate
limiting at 100 ␮M ATP, but the numerical value of the cor-
responding transition rate is considerably higher than the one
corresponding to the force dependent step, hence the ran-
domness parameter approaches one from below at high
loads. At rather high ATP concentrations 共1 and 2 mM curves
in Fig. 9兲, there are essentially two rate limiting steps, the
third and fourth ones, and finally only one at very high loads.
IX. SUMMARY AND CONCLUSIONS
We have presented theoretical arguments aimed at the
identification of the role of applied forces on the kinetics of
motor proteins. The driving principle for our work is the
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Kinetics models for motor proteins 10347
search for consistency between discrete models and continu-
ous ones. In this respect, we have shown that the load de-
pendence of transition rates in mechanochemical systems can
be more complicated than the Arrhenius exponential. We
have provided an analytical method, based on a renormaliza-
tion group scheme, leading to a new formula for the force
dependence of transition states. This formula has been used
to interpret the available data on the kinetics of the motor
protein kinesin, obtaining a remarkable agreement with ex-
perimental results and theoretical predictions for future ex-
periments. We are convinced that the analytical tools devel-
oped for the case of motor proteins, can be easily generalized
to other biological systems and can be useful in a number of
experiments at the single molecule level.
ACKNOWLEDGMENTS
One of the authors’ 共G.L.兲 research has been supported
by a Marie Curie Fellowship of the European Community
Program ‘‘Improving Human Research Potential and the
Socio-Economic Knowledge Base’’ under Contract No.
HPMF-CT-2001-01432. The authors are solely responsible
for information communicated and the European Commis-
sion is not responsible for any view or results expressed.
APPENDIX: DIFFUSION COEFFICIENT
The evaluation of the diffusion coefficient in periodic
systems is an interesting problem in the theory of stochastic
processes, and is also of great importance since experiments
performed on motor proteins usually measure this coeffi-
cient, or the related randomness parameter. The approach
used here is similar to the one proposed by Wang et al.26 for
RNA polymerase and here adapted to our 4 states model. The
procedure has been generalized to models with N states,19,20
and is a valid alternative to the calculations involved in dis-
crete jump processes,6 especially when the discrete steps are
different from each other, as is the case of our model.
We can derive an expression for the effective diffusion
coefficient by examining the evolution of a solution of the
form,
冋 册 冋 册
P 1 共 n,t 兲 c 1共 t 兲
P 2 共 n,t 兲 c 2共 t 兲
⫽e iknp , 共A1兲
P 3 共 n,t 兲 c 3共 t 兲
P 4 共 n,t 兲 c 4共 t 兲
where P i (n,t) represents the probability to be in state i, i
⫽1,2,3,4 in the period n, p is the periodicity of the filament,
c i (t) are unknown functions of time. This is the solution of
Eq. 共6兲. Substituting Eq. 共A1兲 in Eq. 共6兲, we find the time
冋 册冋 册
evolution of the unknown c i (t),
c 1共 t 兲 c 1共 t 兲
d c 2共 t 兲 c 2共 t 兲
⫽A , 共A2兲
dt c 3共 t 兲 c 3共 t 兲
c 4共 t 兲 c 4共 t 兲
where
 10348 J. Chem. Phys., Vol. 117, No. 22, 8 December 2002 G. Lattanzi and A. Maritan

冋 册
⫺ 共 k 1 关 T 兴 ⫹k ⫺4 兲 k ⫺1 0 k 4 exp共 ⫺ik p 兲
k 1关 T 兴 ⫺ 共 k ⫺1 ⫹k 2 兲 k ⫺2 0
A⫽ , 共A3兲
0 k2 ⫺ 共 k ⫺2 ⫹k 3 兲 0
k ⫺4 exp共 ik p 兲 0 k3 ⫺k 4

for model 共b兲. The eigenvalues of the matrix A are the roots D⫽ p 2 b. 共A12兲
of the characteristic polynomial,
For a detailed mathematical proof, the reader is referred
det共 A⫺␭I 兲 ⫽␭ 4 ⫹ ␴ 3 ␭ 3 ⫹ ␴ 2 ␭ 2 ⫹ ␴ 1 ␭⫹ ␴ 0 , 共A4兲 to the work by Koza.19,20 The advantage of such an approach
is that the characteristic polynomial, Eq. 共A4兲 is sufficient to
with
determine the coefficients a and b without detailed knowl-
␴ 3 ⫽k 1 关 T 兴 ⫹k 2 ⫹k 3 ⫹k 4 ⫹k ⫺1 ⫹k ⫺2 ⫹k ⫺4 , 共A5兲 edge of its roots.
Indeed a⫽ ⳵ ␭ 0 ( ⑀ )/ ⳵ ⑀ 兩 ⑀ ⫽0 . This coefficient can be
␴ 2 ⫽k 1 关 T 兴共 k 2 ⫹k ⫺2 ⫹k 3 ⫹k 4 兲 ⫹k 2 共 k 3 ⫹k 4 ⫹k ⫺4 兲 evaluated by writing ␭ 0 ( ⑀ ) in place of ␭ 0 in Eq. 共A4兲 and
⫹k 3 共 k 4 ⫹k ⫺4 兲 ⫹k ⫺1 共 k ⫺2 ⫹k 3 ⫹k 4 ⫹k ⫺4 兲 deriving both sides with respect to ⑀. This derivative is zero,
since ␭ 0 ( ⑀ ) is a root of the characteristic polynomial. There-
⫹k ⫺2 共 k 4 ⫹k ⫺4 兲 , 共A6兲 fore we are left with
␴ 1 ⫽k 1 关 T 兴共 k 2 k 3 ⫹k 2 k 4 ⫹k ⫺2 k 4 ⫹k 3 k 4 兲 ⫹ 共 k ⫺1 k ⫺2 ⳵␭0 ⳵␴ 0
␴1 ⫹ ⫽0, 共A13兲
⫹k ⫺1 k 3 ⫹k 2 k 3 兲共 k 4 ⫹k ⫺4 兲 , 共A7兲 ⳵⑀ ⳵⑀

␴ 0 ⫽k 1 关 T 兴 k 2 k 3 k 4 共 1⫺e ⫺ikp 兲 . 共A8兲 where it is assumed that all derivatives are evaluated at ⑀
⫽0. From Eq. 共A13兲, we get a⫽⫺( ⳵␴ 0 / ⳵ ⑀ )/ ␴ 1 . The coef-
Letting ⑀ ⫽ikp, the roots of Eq. 共A4兲 are given by ficient b is readily found from the second derivative,
␭ 0 ⫽a ⑀ ⫹be 2 ⫹O 共 ⑀ 3 兲 .
The real parts of the other eigenvalues are all negative at
⑀ ⫽0. The effective spatial diffusion, D, is computed from
共A9兲
b⫽
1 ⳵ 2␭ 0
2 ⳵⑀2
⫽⫺
1 ⳵ 2␴ 0
2␴1 ⳵⑀ 2
⫹2 ␴ 2
⳵␭0
⳵⑀
冋 冉 冊 2

⫹2
⳵␴ 1 ⳵ ␭ 0
⳵⑀ ⳵⑀
. 册
共A14兲
the decay rate of the long wave modes k⬇0 of P⫽ P 1 ⫹ P 2
We find
⫹ P 3 ⫹ P 4 . The eigenvectors corresponding to the eigenval-
ues ␭ 1 , ␭ 2 , ␭ 3 are such that P⬇0, so that the decay rates of k 1关 T 兴 k 2k 3k 4
the corresponding eigenmodes do not affect the magnitude of a⫽⫺ , 共A15兲
␴1
long wave modes of P. Thus, these three eigenvalues are not
related to D. The eigenvalue ␭ 0 is responsible for the evo-
lution of long wave modes of P. When the eigenvector cor-
responding to ␭ 0 is taken as the initial value for
b⫽⫺
a
2 冉␴2
1⫹2 a .
␴1
冊 共A16兲

关 P 1 , P 2 , P 3 , P 4 兴 in Eq. 共A1兲, the solution to the master equa- We recognize in the first equation part of the formula for
tion, Eq. 共6兲, is given by velocity, Eq. 共38兲, so that v ⫽⫺a p. From Eqs. 共A11兲 and

冋 册P 1 共 n,t 兲 共A12兲, and its definition, Eq. 共43兲, we obtain the expression
P 2 共 n,t 兲
P 3 共 n,t 兲
P 4 共 n,t 兲
⫽exp ik np⫹冋冉
I共 ␭ 0 兲
k
t ⫹k 2
k2
冊
R共 ␭ 0 兲
t 册 for randomness,

r⫽1⫹2
␴2
a. 共A17兲

冋 册
␴1
c 1共 0 兲 This formula, together with the expressions for ␴ 1 and
c 2共 0 兲 ␴ 2 , Eqs. 共A6兲, 共A7兲, has been used throughout the paper.
• , 共A10兲
c 3共 0 兲
c 4共 0 兲
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where I(␭ 0 ) and R(␭ 0 ) are, respectively, the imaginary and 2
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