Cell Biophysics

Marileen Dogterom, FOM Institute for Atomic and Molecular Physics, Amsterdam,
The Netherlands
Physical processes affect macromolecular interactions in a cellular environment, either by
affecting the free-energy landscape directly or by affecting the physical location and
mobility of interacting molecules in the cell.
Introduction
Proteins and enzymes are the macromolecular workhorses
of living cells. In the cell, macromolecules interact with
each other in specic ways, that allowthe cell toperformits
various functions. Macromolecular interactions are driven
by the favourable change in free energy that occurs when
molecules interact with their substrates, and much of what
we know about the specic action of enzymes is in fact
learned from biochemical assays that characterize these
free-energy changes under standard in vitro conditions.
However, simple biochemistry does not tell the complete
story. Physical processes that occur in the cell can strongly
modify the conditions under which molecular interactions
take place and as such are an integral part of cellular
functioning. Likewise, physical processes that aect the
mobility and spatial distribution of macromolecules in the
cell are important to their biological activity, as they
determine where and when these molecules are brought
into contact with their substrates.
This article rst gives a short description of the interior
of cells, the physical environment in which macromole-
cular interactions take place. Then the concept of free
energy as a driving force behind biochemical reactions is
introduced. Specic and nonspecic eects on the free-
energy levels of interacting macromolecules in a cellular
environment are discussed. Finally, it focuses on processes
that play a role in bringing molecules together in the cell.
The principles of diusionanddirectedtransport drivenby
force generation in the cell are discussed.
The Interior of Cells
Cells come in dierent sizes and shapes. A typical
prokaryotic cell such as the bacterium Escherichia coli
has a rod-like shape and is a few micrometres long. Single-
celled eukaryotes and eukaryotic cells in multicellular
organisms have dierent sizes and shapes depending on
their function, developmental stage or cell-cycle stage. A
typical somatic cell in animals (Figure 1) or plants is a few
tens of micrometres in size. A germ cell such as a frog egg
can be a millimetre in size or larger, andneuronal cells have
outgrowths (axons) that, in a large mammal, can be several
metres long!
To rst approximation, all cells contain the same types
of molecules. These molecules are in general not homo-
geneously distributed throughout the cell but are spatially
organized in a specic way. The level of intracellular
organization diers between prokaryotic and eukaryotic
cells. Eukaryotic cells are more complex and, as described
below, their intracellular organization depends on the
presence of intracellular membranes and the cytoskeleton.
Molecular content of the cell
The most abundant molecule in the cell is water. Every cell
consists of about 70% (by weight) of water and the
Article Contents
Secondary article
. Introduction
. The Interior of Cells
. Different Forms of Energy
. Free Energy and the Criteria of Spontaneous Change
. Enzymes and Energy
. Molecular Interactions in a Cellular Environment
. Macromolecular Crowding
. Thermal Fluctuations
. Random Walks and the Fick Law
. How Enzymes Find Their Substrates
. Forces Generated in Cells
. In Conclusion
1030 m
(1)
(2)
(3)
(4)
Figure 1 Schematic representation of a typical somatic animal cell,
highlighting the organization of the microtubule cytoskeleton (blue lines),
and the relative positions of four subcellular compartments. Typically, the
nucleus is foundnear the centre of the cell (1). The Golgi apparatus appears
as a stack of pancakes close to the nucleus (2), whereas the tubular network
of the endoplasmic reticulum extends throughout the cell (3). The
mitochondria appear randomly dispersed through the cell (4).
1 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
remaining 30% is of a mixture of macromolecules
(proteins, protein complexes, RNA, DNA, polysacchar-
ides), small organic molecules (sugars, fatty acids, amino
acids, nucleotides) and inorganic ions. Despite the fact that
water is suchanabundant component, the macromolecules
in the cell are in fact very densely packed: about 30%of the
volume of cells is occupied by macromolecules (Goodsell,
1998). This means that on average the distance between
neighbouring macromolecules is on the order of their own
size.
Membranes and subcellular compartments
All cells have a plasma membrane toisolate their molecular
contents from the environment. In eukaryotic cells,
intracellular membranes further organize the cell into
functionally distinct compartments such as the cell
nucleus, the mitochondria, the endoplasmic reticulum,
and the Golgi apparatus (Figure 1), lysosomes and
peroxisomes, and vacuoles and chloroplasts in plants.
Many macromolecules are specically localized to these
compartments or to the membrane structures that dene
them. Prokaryotic cells such as E. coli do not have
intracellular membranous compartments, but a certain
level of subcellular organization does exist. The DNA, for
instance, is largely segregated from the cytoplasm in a
DNA-rich area called the nucleoid.
The cytoskeleton
Eukaryotic cells contain a cytoskeleton that consists of
microtubules, actin laments, and intermediate laments.
The cytoskeleton controls shape and rigidity of the cell,
allows for shape changes and cell motility, and is of crucial
importance for the spatial organization of the interior of
the cell. In many cells, for example, microtubules radiate
from the centre of the cell to the plasma membrane,
providing a mechanical basis for the transport and spatial
distribution of intracellular membrane compartments
(Figure 1). Although bacteria have widely been assumed
not to contain any cytoskeletal structures, it is now
becoming clear that at least one bacterial protein, called
FtsZ, shares many properties with eukaryotic tubulin (the
protein subunit of microtubules), among them the ability
to form long lamentous structures (Lutkenhaus and
Addinall, 1997).
Different Forms of Energy
The functioning of a cell depends on specic reactions that
take place between the various types of molecules in the
cell. To predict which molecules can react with each other,
one rst needs toknowsomething about the energy of these
molecules.
The internal energy E of a macromolecule such as a
protein is determined by energy stored in internal chemical
bonds, by noncovalent intramolecular interactions (i.e. by
the conformation of the protein), by the amount of internal
vibrational energy, and by the amount of mechanical stress
in the molecule. When a molecule reacts with another
molecule, its energy will in general change. During this
reaction, work may be performed on the outside world,
heat may be created or adsorbed, and the amount of
disorder in the system (the entropy S) may change. All of
these quantities, combined in the so-called Gibbs free
energy, determine which reactions can, and which reac-
tions cannot occur spontaneously.
Free Energy and the Criteria of
Spontaneous Change
The secondlawof thermodynamics states that a systemcan
change spontaneously only when the sumof the entropy of
the system S
sys
and its surroundings S
surr
(or the total
amount of disorder in the universe) increases as a result of
this change (eqn [1]).
DS
tot
5DS
sys
1DS
surr
4 0 [1]
Combined with the rst law, which states that the amount
of heat added to the system should be equal to the sum of
the change in internal energy and the amount of work
performed on the outside world, the second law translates
into a useful criterion of spontaneous change for any
process occurring in a system at constant pressure P and
absolute temperature T (eqn [2]).
DG5DH2TDS 5 0 [2]
Here DG is the change in (Gibbs) free energy and DS is the
change in entropy of the system. DH is the change in
enthalpy or the amount of heat added to the system, which
is given by DH5DE1PDV, where DE is the change in
internal energy and PDV, the pressure multiplied by the
change insystemvolume, is the amount of workperformed
onthe outside world. Note that apart fromthe temperature
the equation above contains no information about the
surroundings. It can be shown that 2DH/T is a direct
measure of the entropy increase of the surroundings and
that 2DG/T is thus a measure of the total increase in
entropy of the system and its surroundings.
The concentration of reactants influences DG
A (bio)chemical reaction occurs spontaneously if the total
free energy of the system after the reaction is lower than
before the reaction (DG 5 0). This change in free energy
depends not only on the intrinsic (or standard) free energy
dierence between the reacting molecules and their
products but also depends on the concentrations of the
Cell Biophysics
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reactants, owing, for instance, to entropy eects associated
with the mixing of the reacting molecules. For the simple
reaction AB in a dilute solution, DG is given by eqn [3].
G = G
0
k
B
T ln
[B[
[A[
[3[
where DG
0
5G
0
B
2G
0
A
is the dierence in standard free
energy between molecules A and B, k
B
is Boltzmanns
constant, and [A] and [B] are the concentrations of A and
B. At equilibrium, when DG is zero, the dierence in
standard free energy between the molecules A and B is
exactly compensatedby their concentrationdierence (eqn
[4]).
[B[
[A[
= e
G
0
=k
B
T
= K [4[
where K is the so-called equilibrium constant. At
equilibrium, the reaction AB takes place just as often
as the reaction BA, and in this situation neither reaction
leads to a gain in free energy.
For sequential reactions, DG values are
additive
When several reactions take place sequentially, for
instance when the reaction AB is followed by the
reaction BC, then the total free-energy change is given
by the sum of the free-energy changes of the individual
reactions (eqn [5]).
DG
AC
5DG
AB
1DG
BC
5
(G
B
2G
A
) 1(G
C
2G
B
) 5G
C
2G
A
[5]
The free-energy dierence for the complete reaction thus
depends only on the free-energy dierence between the
initial and nal products. This is due to the fact that the
free-energy dierence is independent of the reaction
pathway.
The activation energy controls the reaction
rate
Although the value of DG determines whether a reaction
can occur spontaneously, it does not make any predictions
about the speed of that reaction. A reaction often passes
through one or more intermediate states with free energy
levels that are higher than the free-energy levels of both the
initial and nal product (Figure 2a). These intermediate
states represent a free-energy barrier to the reaction, which
is given by the activation energy DG
act
. To be able to pass
this barrier and form a product, the reactants have to
acquire sucient energy from their surroundings, which
sets a limit to how fast a reaction can occur. In general the
reaction rate is given by eqn [6]:
k
AB
= A e
G
act
=k
B
T
[6[
where A is a pre-exponential factor that depends on the
specic reaction conditions and the rate at which reacting
molecules encounter each other. When DG
act
is much
larger than k
B
T, the reaction becomes very slow and
therefore unlikely to occur spontaneously, even though the
free-energy dierence between the initial and nal product
may be large.
Enzymes and Energy
In cells, biochemical reactions are often mediated by
enzymes. Enzymes increase the rate of certain reactions
relative to others or couple unfavourable reactions to
favourable reactions such as ATP hydrolysis. Among all
the reactions that are in principle possible in the cell, only a
certain number occur at a signicant rate owing to the
specic action of the enzymes that are present.
Enzymes and the lowering of activation
energy
Enzymes act as catalysts that change the rate of
biochemical reactions. By binding reacting molecules in a
specic way, anenzyme provides an alternative pathway to
a reaction, thereby lowering the free-energy level of
intermediate states (Figure 2b). An enzyme thus lowers the
activation energy of a reaction, which causes a signicant
increase in the reaction rate.
Enzymes have no eect on the initial and nal free
energies of the reacting molecules. Therefore, in an
equilibrium situation, the concentrations of the reacting
molecules will be the same in the absence or presence of the
enzyme. However, the rates at which forward and back-
ward reactions occur, as well as the rate at which a reaction
Progress of reaction
F
r
e
e

e
n
e
r
g
y
(a)
Reactants
G
act
G
0
Intermediate
states
Products
(b) (c)
Figure 2 Specific and nonspecific effects on the free-energy landscape of
biochemical reactions in cells. A reference is provided by an uncatalysed
reaction in a dilute solution (a). Enzymes lower the free-energy level of
intermediate states to catalyse the conversion between specific reactants
and products, without altering the free-energy levels of the reactants and
products themselves (b). Macromolecular crowding effects change the
free-energy levels of all reactant, products and intermediate states in
nonspecific way (c).
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will reach its equilibrium situation, will be much higher in
the presence of an enzyme.
Enzymes convert between different forms of
energy
Enzymes can drive reactions that do not occur sponta-
neously by coupling them to energetically favourable
reactions such as ATP hydrolysis. When two reactions are
coupled toeach other, it is the total free-energy change that
determines whether the reaction can take place. Any
reaction requiring less free energy than provided by
hydrolysis of an ATP molecule should therefore be
possible. Enzymes can use the free energy available from
ATP hydrolysis to produce mechanical work, to pump
small molecules or ions against chemical or electrical
gradients, or to drive the biosynthesis of macromolecules.
It is important to note that the hydrolysis of ATP can
only be used as a source of free energy when the hydrolysis
reaction takes place away from equilibrium. If the
concentration of ATP is in equilibrium with the concen-
trations of ADP and inorganic phosphate, then the
hydrolysis of an ATP molecule does not lead to a gain in
free energy. Therefore, to drive other reactions in the cell,
the concentration of ATP has to be kept at a higher level
than its equilibrium concentration.
Tokeepthe concentrationof ATPhighinthe cell, energy
has to be supplied by the outside world. Cells take up
energy fromtheir environment in the formof light or in the
form of small organic molecules derived from food. This
energy is converted into chemical bond energy that is
stored in molecules like ATP.
Molecular Interactions in a Cellular
Environment
The criteria for spontaneous change such as described
above apply to biochemical reactions under idealized
conditions in the absence of catalysts. These are not the
conditions found in the interior of cells. Not only do
enzymes act as specic catalysts, but there are also
nonspecic eects that change the free energy landscape
of biochemical reactions in cells.
Water in cells
The presence of water is important in many ways to the
macromolecular reactions that take place in the cell.
Proteins in the cytoplasmare folded in such a way that they
expose polar or charged groups on their surfaces. These
groups ensure the solubility of the protein in the cytoplasm
by forming favourable hydrogen bonds with surrounding
water molecules. Membrane proteins in general have
partly hydrophobic surfaces, and are consequently less
soluble in water.
When molecules interact with each other, for instance
through the formation of hydrogen bonds, they do this at
the expense of breaking hydrogen bonds with water
molecules. Therefore, their change in energy level depends
not only on the newly formed bonds but also on the loss of
bonds with water molecules. In addition, macromolecular
interactions have an inuence on the ordering of the water
molecules that surround them. Depending on the exact
circumstances, the formation of a complex between two
macromolecules can either increase or decrease the total
entropy of the two molecules and their surrounding water
molecules.
Macromolecular Crowding
While it is clear that water has a profound eect on the free
energy levels of reactants and products in macromolecular
reactions, it is generally less well recognized that the
presence of other molecules can also have important
eects. Although the concentration of reactants involved
in any specic interaction tends to be low, the total density
of non-water molecules in the cell is in fact very high
(approximately 30% by weight). The medium inside the
cell can be referred to as crowded and a crowded medium
provides for a much dierent reaction bath than an
idealized solvent such as pure water. In any given reaction,
the presence of other molecules may aect the free energy
levels of reactants, products, and intermediate states each
in a dierent way (Figure 2c) (Zimmerman and Minton,
1993). As a result, eects due to macromolecular crowding
may alter both reaction equilibria and reaction rates in a
nonspecic way.
Although it is hard to predict the exact eect of
macromolecular crowding on any given macromolecular
interaction, at least twogeneral eects canbe identied: so-
called depletion forces increase the tendency of macro-
molecules to form clusters, and the high density of
molecules slows down macromolecular diusion.
Depletion forces
Every macromolecule in the cell occupies a certain amount
of volume that, owing to the impenetrability of the
molecule, is not accessible for other molecules in the cell.
A so-called excluded volume is created around every
molecule that depends on both the size and shape of the
molecule itself and the molecule it excludes (Figure 3a). For
instance, the centres of mass of two eectively spherical
molecules with radii a and b have to be at least a distance of
a 1b removed fromeach other. By moving large molecules
together, and making the two excluded volumes overlap,
one decreases the total volume that is excluded for smaller
Cell Biophysics
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molecules. As this has a positive inuence on the total
entropy of the system, such eects can lead to so-called
depletion forces or an enhanced attraction between
macromolecules in the cell. Another way to understand
this is that when two large objects surrounded by many
smaller objects are brought close together, the space
between them will be depleted of the smaller objects. In
this situation, the osmotic pressure exerted by the smaller
objects on the large objects is no longer equal on all sides
and the large objects will be pushed together.
Slow macromolecular diffusion
The high density of macromolecules in the cell leads to
steric hindrance, which slows down macromolecular
diusion (see below). In eukaryotes, the presence of dense
networks of cytoskeletal laments may add to this eect. It
is, however, hard to predict the exact eect on the mobility
of the various molecules in the cell. The diusion constant
of proteins in the cytosol had beenmeasured to be about 10
times lower thaninpure water. For small ions, the diusion
constant in the cell is found to be virtually the same as in
pure water.
Thermal Fluctuations
Thermal uctuations are important in biological systems.
A molecule in thermal equilibrium with its surroundings
will frequently gain, lose or transmit energy on the order of
k
B
T. One consequence of this is that molecules in cells are
in constant (thermal) motion, which leads to their diusive
behaviour (see below).
Another consequence is that under the inuence of
temperature any given molecule can easily uctuate
between states that dier on the order of k
B
T or less in
free energy. The probability distribution of nding the
molecule in any possible state is given by the Boltzmann
equation.
The Boltzmann equation
If a given molecule can exist in n dierent states each with
energy E
i
(i 51,2,
_
,n), then the probability P
i
of nding
the molecule in state i is given by the Boltzmann equation
(eqn [7]):
P
i
=
1
Q
e
E
i
=k
B
T
where Q =
X
i
e
E
i
=k
B
T
[7[
The probability of nding the molecule in a state that has
an energy much larger than k
B
T is very small, whereas
states with energies on the order of k
B
T are quite likely to
occur.
This explains why a reaction barrier on the order of k
B
T
in a biochemical reaction such as described above can
easily be overcome. The reacting molecules are quite likely
to acquire enough energy to overcome this barrier simply
as a result of thermal uctuations. But thermal uctuations
also mean that a bond between a molecule and its substrate
may easily be lost under the inuence of temperature if the
binding free energy is not much larger than k
B
T.
Random Walks and the Fick Law
The constant thermal motionof molecules insolutionleads
to frequent collisions with the surrounding solvent
molecules. If eachcollisionchanges the directionof motion
of a molecule randomly, then the trajectory that molecule
follows in space can be described as a random walk
(Figure 3b).
A single random walker
A random walk is given by a sequence of steps of constant
size d spaced by regular time intervals t, where each
subsequent step is taken in a new randomly chosen
direction. One can show that the average distance /that
a molecule performing a random walk travels from its
starting point increases with the square root of time (eqn
[8]):
r = (6Dt)
_
[8[
(a) Depletion forces (b) Diffusion
(c) Directed transport (d) Confinement
Figure 3 Bringing macromolecules together. (a) Depletion forces lead to
an enhanced attraction between large molecules in the presence of small
molecules. The total volumeexcludedtothe small molecules (dashedlines)
is reduced when the excluded volumes of large molecules overlap (purple
shaded area). (b) Molecules in solution perform a random walk owing to
randomcollisions withthe solvent molecules. This leads todiffusive motion
of the molecules. (c) Molecular motors mediate the directed transport of
molecules or small vesicles filled with molecules along cytoskeletal
filaments. (d) The confinement of molecules to domains in membranes (or
other structures) enhances the efficiency of diffusion as a mechanism for
bringing molecules together.
Cell Biophysics
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where D=d
2
/2t is the diusion constant
For a molecule diusing in a homogenous solvent, it can be
shown that the diusion constant is proportional to k
B
T:
D5k
B
T/x, where x, the frictional drag coecient, depends
on the size and shape of the molecule and the viscosity of
the solvent. For a spherical object of radius a in a simple
uid the drag coecient is given by x 56pZa, where Z is the
viscosity of the uid.
Multiple random walkers
The thermal diusion of individual molecules in solution
has consequences for spatial and temporal variations in
molecular concentrations. In any concentration gradient,
more molecules tendtodiuse fromthe highconcentration
region to the low concentration region than vice versa,
resulting is a net ux J of molecules along that gradient.
This ux can be calculated using the Fick law, which for
one dimension is given by eqn [9]:
J = D
dC(x)
dx
[9[
where C(x) is the concentration of molecules
As a result of this ux, the local concentration changes as a
function of time according to the diusion equation [10]:
@C
@t
=
@J
@x
= D
@
2
C
@x
2
[10[
This equation can be generalized to three dimensions,
where the ux becomes a three-dimensional vector and
each of the three components is dened in a similar way
(Berg, 1993).
Ina closedcontainer, diusionwill eventually leadtothe
formation of a homogeneous concentration, unless con-
centration gradients are sustained by localized sources or
sinks of molecules.
How Enzymes Find Their Substrates
Groups of enzymes that promote specic biochemical
reactions in the cell are usually tied together in reaction or
signalling pathways. Often, an enzyme is activated at a
specic location in the cell, for instance near a receptor
molecule in the cell membrane, after which it has to nd its
way to a substrate located elsewhere in the cell. The
physical location and mobility of the molecules involved in
any given pathway are therefore relevant parameters in
determining cellular functioning.
Diffusion
The delivery of enzymes to their substrates is in many cases
mediated by diusion. This has the advantage that on their
diusive journey through the cell the active enzymes may
encounter and interact with multiple substrates, which
gives the possibility of signal amplication. Diusion is an
ecient means of transportation when the distance to be
travelledis relatively short. It will take a typical proteinof a
few nanometers size about 0.03 s to travel 1 mm, the size of
an E. coli (assuming a diusion constant of 5 mm
2
s
21
).
However, the time required to travel a certain distance
increases quadratically with that distance (see earlier). It
would take the same protein about 80 s (more than 1 min)
to travel a distance of 50 mm, and more than 9 h to travel a
distance of 1 mm! If, for instance, the transport of
macromolecules through the long axons of neuronal cells
had to rely on diusion, they would for all practical
purposes never arrive.
Confinement and complex formation
Diusion clearly has its limitations as a mechanism for
transporting molecules over large distances in the cell. One
way of reducing diusion times is to conne interacting
molecules to subcellular compartments, to the two-
dimensional plane of a membrane or to a one-dimensional
cytoskeletal lament. In fact, many groups of enzymes are
localized to the plasma membrane, to specic intracellular
membranes or to the cytoskeleton. There is increasing
evidence that, within membranes, enzymes are further
organized into small domains, and that diusive processes
are conned to these domains (Figure 3d) (Kusumi and
Sako, 1996). Many enzymes in addition tend to form
complexes in which multiple reactions take place sequen-
tially at the same location, thereby bypassing the diusive
process altogether (Bray, 1998).
Forces Generated in Cells
Forces generated in cells play an important role in many
cellular processes, ranging from muscle contraction and
cell motility to intracellular transport and cell division. In
addition, intracellular forces can direct the linear transport
of molecules through the cell, providing an ecient
alternative to random transport through diusive pro-
cesses (Figure 3c).
At least two types of force-generating mechanisms can
be distinguished: mechanisms that involve molecular
motors, and mechanisms that involve the polymerization
of protein laments.
Molecular motors
So-called linear molecular motors are enzymes that
transport cargo along linear laments such as cytoskeletal
polymers or DNA, thereby converting free energy avail-
able from the hydrolysis of ATP into mechanical work.
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Well-known examples are myosin, which interacts with
actin laments, and kinesin, which walks along micro-
tubules (Howard, 1997). RNA and DNA polymerases are
also linear motors that generate signicant force when
transcribing or copying DNAsequences. Aside fromlinear
motors, there are rotary motors such as the bacterial
agellar motor and ATP synthase, which use a proton
gradient across a membrane the proton motive force as
their source of free energy.
Polymerization forces
Analternative source of force generationis providedby the
free energy available fromthe assembly and disassembly of
cytoskeletal polymers. For example, pushing forces
created by the polymerization of actin are believed to
contribute to the protrusion of the leading edges of
crawling cells (Cramer et al., 1994). Pushing and pulling
forces created by growing and shrinking microtubules are
believed to play a role in the motion of chromosomes
during mitosis (Inoue and Salmon, 1995).
In Conclusion
It should be clear that in a cellular environment the free-
energy landscape of macromolecular interactions can be
strongly inuenced by the presence of other macromole-
cules. Such eects will change the reaction rates and
equilibria of biochemical reactions and may lead to
nonspecic clustering of large molecules.
Whether interactions between specic molecules will
occur at any signicant rate will inadditiondependontheir
mobility and physical location in the cell. The presence of
subcellular compartments provides a structural basis for
the connement and spatial distribution of molecules, and
diusion and directed transport along cytoskeletal la-
ments mediate the transport of molecules within and
between these compartments.
However, many questions remain about the cellular
strategies for bringing molecules together at the right time
and the right place. While it is clear that many molecules
are not at all homogeneously distributed through the cell,
in many cases it is not yet clear what exactly the (physical)
mechanisms are that contribute to this nonhomogeneous
distribution. The (transient) self-assembly and self-orga-
nization of macroscopic structures such as described for
the mitotic spindle (Heald et al., 1996) is likely to be such a
mechanism. The formation of diusive gradients of
molecules or activities may be another.
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Further Reading
Atkins PW (1997) Physical Chemistry, 6th edn. London: WH Freeman.
Berg H (1993) Random Walks in Biology. Princeton, NJ: Princeton
University Press.
Bray D (1998) Signaling complexes: biophysical constraints on
intracellular communication. Annual Review of Biophysics and
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