Thermodynamics and kinetics of molecular motors

R. Dean Astumian
Department of Physics and Astronomy, University of Maine, Orono, Maine 04469-5709, USA
Departnent of Physics, University of Munich, Amalienstrasse 54, 80799 Munich, Germany
(Dated: September 14, 2009)
Molecular motors are first and foremost molecules, governed by the laws of chemistry rather than of mechanics.
The dynamical behavior of motors based on chemical principles can be described as a random walk on a network
of states. A key insight is that any molecular motor in solution explores all possible motions and configurations
by thermal noise, even at thermodynamic equilibrium. By using chemical design and input energy to constrain
motion, and to prevent motion that is not wanted, what is left behind is the motion that is desired.

Introduction

Much work on molecular motors has been inspired by a

single, central, question - what is the mechanism by which a
molecular motor uses energy from ATP hydrolysis or some
other chemical reaction to cause forward motion and generate
a forward directed force? In this review I will focus on a different question - what is the mechanism by which a molecular
motor uses energy from ATP hydrolysis or some other chemical reaction to prevent backward motion even in the presence
of a backward directed force? To understand the subtle but
very important differences between these two questions, and
the descriptions that naturally arise from attempts to answer
them, let us compare a very small macroscopic motor with a
molecular motor, both at equilibrium.
In his seminal talk in 1959, Plenty of Room at the Bottom, Richard Feynman offered a $1,000 reward to the first
person to construct a motor that would fit in a cube 1/64th of
an inch on a side, not counting wires and power source. This
reward was claimed within a year by an engineer, William
McClellan. When turned off, the motor does what we expect
at static equilibrium - nothing. The motor must be connected
to a power supply to get any motion at all.
Now, consider a molecular motor in aqueous solution, e.g.,
kinesin, at chemical equilibrium where the chemical potentials of ATP and of ADP are equal, ATP = ADP . The
kinesin molecule moves to and fro, sometimes stepping left,
sometimes stepping right, sometimes binding ATP and hydrolyzing it to ADP and Pi, and sometimes binding ADP
and Pi and synthesizing ATP. The dynamic chemical equilibrium is maintained because each forward process is exactly
as likely as the microscopic reverse of that process - on average, for every ATP hydrolyzed there is an ATP synthesized,
and for every step to the right taken by the motor, there is a
step to the left. Importantly, every motion that we associate
with the normal function of the molecule under physiological
conditions - hydrolysing one ATP while taking one step to the
+ end of the microtubule track - is present also at chemical
equilibrium. At equilibrium, however, each reverse motion
is as likely as the forward motion.
What happens when we remove ADP (or add ATP) so that

E-mail:astumian@maine.edu

AT P >> ADP ? Do the states accesible to the molecule

change? Certainly not - there is no way for an individual kinesin molecule to sense the bulk chemical potentials of ATP
and ADP. Similarly, the character of motion by which the protein undergoes a transition from one state to another does not
change when the system is removed from chemical equilibrium by taking away ADP (or by adding of ATP). The only
thing that changes is the relative likelihood that a kinesin
molecule in which the active site for ATP hydrolysis is unoccupied will next bind ATP rather than ADP. Remarkably, this
single change in the boundary conditions for the stochastic
process results in a situation where the motor, in the absence
of load, takes one step to the + end of microtubule for each
ATP hydrolyzed, with almost deterministic precision.
In this mini-review I will discuss the implications of the ineluctable stochasticity of molecules due to interactions with
their thermal environment for understanding the mechanisms
of molecular motors and pumps. The focus will be on development of a framework for description of molecular motors
rather than on interpretation of experimental results for any
particular motor in terms of its structure or kinetics. Much
of the discussion will be inspired by recent synthetic molecular motors such as DNA walkers, catenane based molecular
motors, and synthetic molecular rotors, since, by design, the
mechanisms of motion of these compounds are relatively well
understood.

Stochastic cycles of molecular motors

Many molecular motors [? ? ] convert chemical energy

into directional motion along a polar track (with ends designated + and -), possibly against an applied force. This
is accomplished by coupling the chemical transformations involved in the catalytic conversion of a fuel molecule (S) to
waste product (P) with the conformational transitions of the
motor molecule to form a conformational cycle in which the
protein fluctuates away from and then regresses back to some
initial conformational state [68? ]. Consider, for example,
a two headed motor such as kinesin or myosin V and arbitrarily choose as an initial state a configuration in which both
heads are attached to the track and in which there is nothing
bound at the active site for ATP hydrolysis. Whether at, or
far from, thermodynamic equilibrium, the motor will certainly
fluctuate away from this initial state, possibly by binding fuel

2
(S=ATP) or by binding product (P = ADP) or by dissociating the front head, or by dissociating the back head, etc.. It
is equally certain (unless it dissociates from the track altogether) that eventually the motor will return to the initial state
where both heads are attached and nothing is bound at the active site. Aside from non-productive cycles - those excursions
in which there is no change in the environment - there are several possible outcomes in the environment for each productive
conformational cycle. We define a forward coupled process
(F) as a conformational cycle that involves conversion of one
molecule of chemical fuel (substrate = S) into one molecule
of waste product (product = P) while taking one step towards
the + end of the polymeric track. There are many possible
paths - sequences of positions and chemical states - by which
a forward process can occur. One such path is shown as the
solid curve in Fig. 1a. For each possible forward path there is
a microscopic reverse path ( FR ) - the movie of the forward
path played backward - in which the sequence of positions and
states in the forward trajectory is exactly reversed, and hence

a)

FR

CR

in which one molecule of P is converted into one molecule

of S while taking one step in the - direction, shown as the
dotted curve in Fig. 1a. There is also a coupled backward
process (labeled B) in which one molecule of S is converted
into one molecule of P while the motor takes one step in the
- direction, shown as the dashed curve in Fig. 1a. For each
backward path there is also a microscopic reverse path (BR )
in which one molecule of P is converted into one molecule
of S while the motor takes one step in the +-direction (not
shown in Fig. 1a). In addition to the coupled transitions, there
are also paths (denoted C) in which a molecule of substrate
is converted to product without stepping in either direction
and the reverse (CR ) in which a molecule of P is converted
to S without taking a step, and there are paths in which the
motor takes a step to the + end of the track without interconversion of S and P (denoted S) and reverse paths (SR ) in
which the motor takes a step to the - end of the track without
inter-conversion of S and P.

b)

BR

FR

2free

1free

CR

2free

1free

BR

2free

SR

Chemistry

Chemistry

2bound 1bound 2bound 1bound 2bound

SR 2free

2free

1free

2free

2bound 1bound 2bound 1bound 2bound

1free

2free

1free

2free

1free

2free

Position

Position
FIG. 1:

The ratio of the probability for a process and its microscopic

reverse is set by thermodynamics [27? ] (see the section on
detailed balance),
Coupled
Uncoupled

+LF
PF
= e kB T ;
PFR

PC
= e kB T ;
PCR

LF
PB
= e kB T
PBR
LF
PS
= e kB T
PSR

the Boltzmann constant and the Kelvin temperature. Equations (1) follow from microscopic reversibility [27] and are
model independent.

(1)

where = S P is the difference in the chemical

potentials of the substrate and product, F is the component
of the load force along the track (we take positive force to
be in the + direction), L is the step size along the track,
kB T ( 4 1021 J at room temperature) is the product of

The total probability, P+ that any given productive conformational cycle will result in a step in the + direction, the
total probability P that any given productive conformational
cycle will result in a step in the - direction, and PSP and
PPS , the total probabilities for conversion between S and P,

3
are
P+ = PF + PB R + PS
P = PFR + PB + PSR
PSP = PF + PB + PC
PPS = PFR + PBR + PCR

(2)

between S and P is hNchem i = PSP PPS . The average

velocity of the motor is v = L hNstep i /cyc and the average rate of conversion of S to P is r = hNchem i /cyc , where
cyc is the average time for completion of a productive cycle.
We can use Eq. (1) to write the probabilities for the reverse
processes (PFR , PBR + PSR ) in terms of the forward process
(PF , PB + PS ) to obtain

The average number of steps per conformational cycle is

hNstep i = P+ P , and the average number of conversions

v=



1e

LF
kB T

 P 
 P
+LF
LF
PB 
S
F
kB T
kB T

+
1e
1e
PF
PF
cyc

LF
kB T

 P 
 P
+LF

PB 
C
F
kB T
kB T
+
1e
+
1e
PF
PF
cyc

(3)
r=



1e

Equations (2) and (3) are in the best traditions of theoretical

physics - rather general (they can be used to describe any two
chemically coupled transport processes) - and in and of themselves not very useful for calculations since the time constant
and the ratios of probabilities involved are functions of the
forces and can only be derived in the context of a model or obtained from experiment. Nevertheless, a few salient features
emerge. First, we recognize that the ratios of probabilities
(PB /PF , PS /PF , and PC /PF are sufficient to calculate the
effective stoichiometry ( hNstep i / hNchem i), the efficiency (
hNstep i F L/(hNchem i ), and the ratio of forward to backward steps P+ /P+ , while to calculate the rate (r) and velocity
(v), and the output and input power (v F and r SP ,
respectively) we also need the average time needed for a productive conformational cycle, cyc . A second salient feature
of the theoretical framework is the presence of a backward
process, B, in which ATP is hydrolyzed as a mechanism for
stepping to the - end of the track in addition to the forward
reverse process, FR , in which ATP is synthesized.
A theoretical prediction supported by experiment: Martin Bier
and I made the striking prediction in 1996 that back-stepping
of a molecular motor such as kinesin does not necessarily
involve synthesis of ATP. On the basis of a kinetic Brownian motor model (Fig. 1b, where in the earlier paper only
one quadrant was drawn since that contains a full period, and
hence all information), we observed that as an external force
is applied, the system responds by changing the stoichiometry. Interestingly, a large applied force actually stimulates
ATP hydrolysis. This is in striking opposition to predictions
based on completely coupled single-cycle models prevalent
both then [? ] and now [? ] that predict that backstepping can
only arise by reversal of the single-cycle and hence should
be inexorably accompanied by ATP synthesis and thus inhibited by ATP. The behavior predicted by Bier and Astumian
has now been observed experimentally by Carter and Cross [?
] who showed that back-stepping in the presence of a large

force is stimulated rather than inhibited by ATP, and it was

suggested that the back-stepping may be accompanied by ATP
hydrolysis. The observed behavior is a predicted signature of
a gently coupled Brownian motor mechanism, in which the
preferred mechanism (pathway through the states) shifts under the influence of changing environmental conditions such
as the applied force [? ]. The model in Fig. (1b) is a minimal
Brownian motor since only two mechanical states (1 and 2,
which for a two-headed motor can be interpreted as the number of heads attached to the track) and two chemical states
(bound and free) are used - a total of four states. A number of
recent authors [? ? ] have proposed after the experiments of
Carter and Cross similar models to that of Astumian and Bier,
but with many more states (up to seven or eight) in efforts to
fit experimental curves, with very good success.
Summary of the theoretical framework: The theoretical description presented in this paper focuses on the relative probabilities of two coupled processes - forward, F and backward
B and their reverses, FR and BR , respectively, and on two
uncoupled processes S and C, and their reverses SR and CR ,
respectively. The probabilities for these processes are related
by time and space symmetries of the system.
At thermodynamic equilibrium PF = PFR and PB =
PBR . This time symmetry constraint follows from the principle of microscopic reversibility and is broken when and/or
F are not zero. When + F > 0, PF > PFR , and when
F > 0, PB > PBR .
In an isotropic environment, irrespective of whether the system is at or away from thermodynamic equilibrium, the relative likelihood of a backward process to a forward process is
governed solely by the exponential of the force PB = PF eF ,
and the relative likelihood of backward-reverse process to a
forward-reverse process is similarly PBR = PFR eF . In
such an isotropic system, if F = 0 then v = 0 irrespective
of the value of . Spatial symmetry breaking is achieved
by appropriately designed structures - polar tracks and broken

4
mirror symmetry in the case of biomolecular motors.
The uncoupled processes S, SR , C, and CR (often termed
slip processes) modify the quantitative but not qualitative
behavior of the system.
Now let us consider how we can engineer a system to undergo directional motion in response to a chemical potential
gradient > 0, at first not in terms of structure, but rather
in terms of energetics - the heights of barriers between (lability) and the relative energies of (stability) the states of the
system in the minimal Brownian motor, Fig. 1b.

A Minimal Brownian Motor

The lattice model in Fig. 1b can be written in a more compact form as

2b

1b

2f

2b

2f

1f

1b

able to step backward which would be energetically difficult

for a completely coupled single cycle mechanism.
A mechanism with
2bound

[1bound ]

2bound

[2free ]

1free

[2free ]

By incorporating bi-lability (open or closed) in the transition rates and bi-stability ( stable [ij ] or unstable ij ) in the
energies of the states directional (horizontal) transport occurs
when the vertical cycle is powered by the chemical fuel. The
skeleton graphs for the forward and forward reverse path
F(FR )

o
2bound
I

/ [1bound ]
U


[2free ]

1free o

2b

1f

2f

where all possible transitions are shown and the cycles connecting the upper (bound) states and the lower (free) states
GGGB
GGGB
describe a catalytic process S + Ff F
GG Bb S F
GG Ff + P

/ [2free ]

and for the backward and backward reverse path

BR (B)

o
2bound
U

/ [1bound ]
I

[2free ]


1free o

which can be written

/ [2free ]

S
%(
9 Bb

y
Ff e
P

F, B = 1, 2

engineering with stability and lability

We can achieve chemically driven directed motion by two

functions very familiar to chemists - kinetically blocking selected transitions to gate flow, and switching the relative stabilities of the two mechanical states 1 and 2 depending on
whether the active site is occupied (bound) or not (free). A
very straightforward case is that in which all transitions except for a single cycle are blocked, e.g.,
2bound

1bound

2bound

2free

1free

2free

resulting in a completely coupled single cycle where PB =

PBR = PC = PCR = PS = PSR = 0. Such a cycle can have
an efficiency of unity, and the only possibility for driving the
motor backwards involves converting P to S (i.e., synthesis of
ATP for most biological motors). This may be a good description, e.g., of the F0F1 ATPase, where forcing the F1 subunit
backward does in fact synthesize ATP. For molecules whose
major function is transport or motion it is advantageous to be

as well as several uncoupled cycles C/CR and S/SR . When

the chemical potential of substrate is higher than that of product the directional flow of S P breaks detailed balance that
at equilibrium would preclude directional motion [55]. As the
applied force increases, eventually despite having the states
2free and 1bound . If the kinetic block is not absolute, then obviously the motor can move directionally in an external force
even without S or P, but the presence of S and P, even at chemical equilibrium, will increase the rate of motion by allowing
the motor to switch back and forth to move through the kinetic
gates without having to surmount the high barriers. This was
observed by Yildiz et al. [? ] who showed that kinesin can
move backward and forward under the action of an external
force even in the absence of nucleotide, but that the motion
is much more rapid when ADP was added. All of this behavior - backstepping, force induced motion in the absence of
nucleotide, increase in force-induced stepping rate in the presence of product (ADP) are expected from the perspective of a
loosely coupled brownian motor mechanism [? ] but not consistent with either a single completely coupled kinetic cycle
mechanism [? ], nor with an obligatory ATP-induced power
stroke mechanism [? ].

2bound

[1bound ]

2bound

[2free ]

1free

[2free ]

5
(-)c-dc-dc-dc-d(+), where a binds tightly to c
and b binds tightly to d. The dimer has mirror symmetry when extended while the track has translational (periodic),
but not mirror, symmetry. If the linker between the two a-b
monomers is long enough to allow two a-c and two b-d interactions, but not so long that the linker can adopt a totally random configuration when the dimer is bound to the track, the
combination of mirror with translational symmetry guarantees
that, when bound, the front a-b monomer will not be equivalent to the rear a-b monomer (See Fig. 1). In order to bind
both dimers, the linker itself adopts a somewhat strained
configuration but the free energy of the molecule as a whole is
minimized when both monomers are bound unless the linker
is very short such that the strain energy would be greater than
the interaction energy between b and d.

By removing the kinetically blocked transitions from the

diagram we see that, in contrast to the energy ratchet, the optimal information ratchet is described by a single completely
coupled path
F/FR

o
2bound
I

/ 1bound
U


2free

1free o

/ 2free

2bound

[1bound ]

2bound

[2free ]

1free

[2free ]
Let a-b held together at the fixed distance c-d form a catalytically active complex and let substrate binding cause dissociation of a-b from c-d (See Figure 1). Note that even if the
track is not polymerized binding a-b to free c-d monomers in
solution will still activate the catalysis of S P.

A simple symmetry based hand-over-hand molecular motor

Consider a simple model with a flexible dimeric motor

molecule, a-bb-a, that interacts with a rigid polymeric track,

C D

a b
c d

c d

c d

c d

a b
c d

c d

Backward Process

c d

c d

c d

a b
a b
c d

c d

c d

c d

c d

a b
a b
c d
c d
Futile Cycle

c d

c d
P
a b

III. Dissociate product

and reattach

a b
c d

I. Bind Substrate
And Detach

II. Diffusive Seach

and convert S to P

a b
c d

2f

c d

a b
c d

a b
c d

A B
C D

a b
c d

1b

c d

P
c d

c d

c d

a b
c d

Forward Process

a b
c d

FIG. 2: Simple mechanism for undirectional motion of a dimeric polymer on a rigid track.

In step I, the substrate binds to the stably bound dimer causing

that monomer to which S associates to detach from the track.
Although the two dimers are a priori equivalent in solution,
the probability for S to bind to the front a-b may well be significantly less than the probability for S to bind to the rear
monomer since the configuration of linker in the region of the
two bound monomers will be quite different and may sterically hinder binding at the front monomer. We parametrize
this kinetic splitting by a term .
In step II, substrate is converted to product at the active site,
and the now free monomer diffusively explores its available
configuration space. If, as seems likely, some elastic energy

was stored in the linker near the front monomer, the free head
will, in the absence of an applied force, most likely be in front
of the bound head, and hence when product is released, will
most likely rebind to the front . We parametrize the kinetic
splitting for rebinding to the front vs. rear by a factor . The
process in which the rear monomer, once detached, moves in
front of the remaining attached monomer due to stored elastic energy is often termed a power stroke in the literature
of bio-molecular motors. If substrate or product binds to the
still attached monomer while one head is detached the motor
dissociates entirely from the track. For simplicity we ignore
this possibility in this paper.

6
The path probabilities can be written in terms of the probabilities of the elementary events: binding substrate to the
front or rear monomer and detaching from the track (p(+S, f )
or p(+S, r), respectively); binding product to the front or
rear monomer and detaching from the track (p(+P, f ) or
p(+P, r), respectively); releasing substrate and reattaching to
the front or rear (p(S, f ) or p(S, r), respectively); and releasing product and reattaching to the front or rear (p(P, f )
or p(P, r), respectively). These elementary events and how
they lead to completion of one of the eight possible paths can
be illustrated in terms of a 2-D lattice model similar to that
proposed by Bier et al. [73], where the motor, starting in the
center executes a random walk on the lattice until completing
one of the eight possible processes shown
These relations can be used to interpret the ratios of the
forward to reverse stepping obtained in single molecule experiments, and also the completions of substrate to product
conversions vs. product to substrate conversions when experiments that allow this quantity to be directly determined are
designed. The parameters and reflect the relative importance of a Brownian motor mechanism vs. a power stroke
mechanism. A motor with << 1 and 1 operates almost
entirely based on a power stroke, where the bias to the motion
arises solely from the repositioning of a detached monomer
near the front rather than rear binding site due to stored elastic
energy. On the other hand, a motor with 1 and << 1
can be thought of as a Brownian motor since the physical motion of a detached monomer occurs almost entirely by diffusion, and the bias to the motion arises because of the greater
probability to bind substrate to (and hence cause detachment
of) the rear monomer.
In Figure two we delineate the different working regimes of
the system by plotting curves of P+ /P = 1 (solid line) and
(PSP /PP S ) = 1 (dashed line) on a graph with as the
horizontal coordinate and F as the vertical coordinate.
a) In region Im the motor uses energy from energetically
downhill conversion of S to P ( S > P ) to drive + directed motion against a --directed force; b) in region Ic,
the motor uses energy from downhill - -directed stepping to
drive energetically uphill conversion of P to S ( S > P ); c)
In region IIm the motor uses energy from energetically downhill conversion of P to S ( P > S ) to drive - -directed
motion against a +-directed force; d) in region Ic, the motor uses energy from downhill + -directed stepping to drive
energetically uphill conversion of S to P ( P > S ).
The parameters used in Fig. 2, = .25 and = .005, are
consistent with a predominately Brownian motor. The plot
does not change significantly if we take = 1, eliminating
the power stroke component altogether. As shown, the stopping force is close to the thermodynamic limiting value. Interestingly, the polymer is a much poorer + - directed motor

when we take the reverse situation, = .005 and = .25

to give a predominately power stroke mechanism for directed
motion. To achieve a reversible motor - a motor that can effectively use chemical energy to drive uphill mechanical motion
and that uses downhill mechanical motion to store chemical
energy - both the Brownian motor ( << 1) and the power
stroke ( << 1) mechanisms are necessary, with the limiting
ideal case that both parameters are zero shown by the dotted
line in Fig. 2. A possible synthetic approach to achieve this
ideal case has recently been suggested by Wang [? ].
A key point of the present paper is the distinction of a backward process, in which a molecule of fuel is consumed and
the motor takes a - directed step, from a reverse process in
which a molecule of fuel is synthesized and the motor takes
a - directed step. A - directed load often predominately
accentuates the backward process, and hence adding substrate
S can stimulate - end directed stepping. This was predicted
by Astumian and Bier [55] based on a Brownian motor model
and has been observed recently by Carter and Cross [56] for
kinesin stepping on microtubule. Further, the stopping force
(that force at which P+ = P ),

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Fstop = ln

(1 + e )(1 + )
(1 + )(e + )

(4)

is in general less than the thermodynamic maximum value

, as seen for kinesin, which has a stopping force of
5pN while the thermodynamic value /L = 80 pN nm/
8 nm 10pN.
It has also been shown that the average time for completion
of a process is the same as the average time for completion of
the microscopic reverse of that process [27? ] irrespective of
the magnitudes of the thermodynamic forces ( and F L in
the case of a molecular motor)
F = FR ;

B = BR ;

C = CR ;

S = SR ;

(5)

conclusion

In an amusingly titled article in Cell, Fifty ways to love

your lever, Steve Block makes the quixotic, but prescient,
statement that the kinesin lever may be more like a leash
than a pry bar. The function of a pry bar is to transmit force
and hence cause desired motion. In contrast, a leash functions
to prevent unwanted motion. It is certainly true for synthetic
motors, and I think that it is true for biological motors as well,
that the over-riding design principle is based on preventing
backward movement so that brownian motion takes the motor
forward where we want it to go.

7
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