pressure depending on the depth: it tends to be compressed in the head group and central acyl chain
regions, and to expand at the junction between the two, which may modulate conformational equilibria
(Marsh 1996). Molecules that dissolve into lipid bilayers may modify the profile of this pressure
gradient and, thereby, affect protein function. The bilayer being free to expand or compress as a whole,
the net overall pressure is just the atmospheric pressure.
The environments experienced by ions, small molecules, and macromolecules such as proteins
in an aqueous phase vs. in the core of lipid membranes are so different that it has a dramatic effect on
their solubility and their interactions with themselves and with one another. The main differences
between the cytosol and membrane interior that are relevant to the organization and interactions of
proteins are summarized in Table 1.2. A major factor is the difference in dielectric constant, ε: it is very
high in water, a highly polarizable medium, and very low in the core of the bilayer. A consequence of
this is that, as already mentioned, ions and polar molecules have a low solubility in the core of a lipid
bilayer, another that ionic interactions are much stronger there than they are in water. In bulk water, a
hydrogen bond between the >N–H group of a peptide bond and the O¼C< group of another, for
instance, can be easily displaced by water molecules at almost no free energy cost, but it requires
4–6 kcalÁmol
À1 to break it in the center of a bilayer (Table 1.2). In terms of an equilibrium constant, a
difference of 5.4 kcalÁmol
À1 entails, at 298 K, a factor of ~10
4 in equilibrium constants in favor of the
state where the hydrogen bond is satisfied. There is, therefore, an enormous thermodynamic pressure
toward (i) excluding polar groups from the hydrophobic core of a lipid bilayer and (ii) bringing
together complementary charges or partial charges that are being forced there, such as by forming salt
bridges or hydrogen bonds (Table 1.2).
1.3
Membrane Protein Functions
Schematically, lipids provide a barrier against the free circulation of ions and polar molecules between
the cytosol of a cell and the exterior fluid, as well as between the interior and exterior of cell
compartments, whereas membrane-spanning proteins take care of actively transporting solutes or
letting them diffuse passively in a controlled manner. These conceptually simple (but often mechanistically extremely sophisticated) operations are at the heart of a host of functions of membrane proteins
(MPs), a few examples of which only can be listed here:
• Facilitating the passive diffusion of polar molecules or ions. Such is the role, for instance,
of the porins of outer bacterial membranes, which act as a sieve, letting diffuse into the
periplasm molecules that are smaller than a given size, with or without any specificity, such as
that for sugars. Similarly, potassium channels in the plasma membrane of animal cells let K
+
ions diffuse from the cytosol, where they are more concentrated, toward the exterior of the
cell. This sets up a transmembrane potential, negative inside, which increases until K
+ ions
have reached their equilibrium electrochemical potential: when the transmembrane potential
reaches, typically, 60–80 mV, the inward and outward passive fluxes of K
+ ions equilibrate.
• Regulated passive diffusion is a very frequent function. It is essential, for instance, in
signaling. In the nerve or muscle plasma membrane exist voltage-sensitive Na
+
-specific
channels, which are normally closed but open in a transitory way when the membrane
potential drops below a given threshold. The resulting massive entry of Na
+ ions entails an
inversion of the membrane potential, which becomes positive inside. Thus, a partial and local
depolarization, such as is created at a neuronal synapse or a neuromuscular junction by
chemical signaling (see below), sets off a depolarization wave, the “action potential,” which,
by activating neighboring sodium channels, can propagate meters away the information that
8
1 Membrane Proteins and Their Natural Environment
regions, and to expand at the junction between the two, which may modulate conformational equilibria
(Marsh 1996). Molecules that dissolve into lipid bilayers may modify the profile of this pressure
gradient and, thereby, affect protein function. The bilayer being free to expand or compress as a whole,
the net overall pressure is just the atmospheric pressure.
The environments experienced by ions, small molecules, and macromolecules such as proteins
in an aqueous phase vs. in the core of lipid membranes are so different that it has a dramatic effect on
their solubility and their interactions with themselves and with one another. The main differences
between the cytosol and membrane interior that are relevant to the organization and interactions of
proteins are summarized in Table 1.2. A major factor is the difference in dielectric constant, ε: it is very
high in water, a highly polarizable medium, and very low in the core of the bilayer. A consequence of
this is that, as already mentioned, ions and polar molecules have a low solubility in the core of a lipid
bilayer, another that ionic interactions are much stronger there than they are in water. In bulk water, a
hydrogen bond between the >N–H group of a peptide bond and the O¼C< group of another, for
instance, can be easily displaced by water molecules at almost no free energy cost, but it requires
4–6 kcalÁmol
À1 to break it in the center of a bilayer (Table 1.2). In terms of an equilibrium constant, a
difference of 5.4 kcalÁmol
À1 entails, at 298 K, a factor of ~10
4 in equilibrium constants in favor of the
state where the hydrogen bond is satisfied. There is, therefore, an enormous thermodynamic pressure
toward (i) excluding polar groups from the hydrophobic core of a lipid bilayer and (ii) bringing
together complementary charges or partial charges that are being forced there, such as by forming salt
bridges or hydrogen bonds (Table 1.2).
1.3
Membrane Protein Functions
Schematically, lipids provide a barrier against the free circulation of ions and polar molecules between
the cytosol of a cell and the exterior fluid, as well as between the interior and exterior of cell
compartments, whereas membrane-spanning proteins take care of actively transporting solutes or
letting them diffuse passively in a controlled manner. These conceptually simple (but often mechanistically extremely sophisticated) operations are at the heart of a host of functions of membrane proteins
(MPs), a few examples of which only can be listed here:
• Facilitating the passive diffusion of polar molecules or ions. Such is the role, for instance,
of the porins of outer bacterial membranes, which act as a sieve, letting diffuse into the
periplasm molecules that are smaller than a given size, with or without any specificity, such as
that for sugars. Similarly, potassium channels in the plasma membrane of animal cells let K
+
ions diffuse from the cytosol, where they are more concentrated, toward the exterior of the
cell. This sets up a transmembrane potential, negative inside, which increases until K
+ ions
have reached their equilibrium electrochemical potential: when the transmembrane potential
reaches, typically, 60–80 mV, the inward and outward passive fluxes of K
+ ions equilibrate.
• Regulated passive diffusion is a very frequent function. It is essential, for instance, in
signaling. In the nerve or muscle plasma membrane exist voltage-sensitive Na
+
-specific
channels, which are normally closed but open in a transitory way when the membrane
potential drops below a given threshold. The resulting massive entry of Na
+ ions entails an
inversion of the membrane potential, which becomes positive inside. Thus, a partial and local
depolarization, such as is created at a neuronal synapse or a neuromuscular junction by
chemical signaling (see below), sets off a depolarization wave, the “action potential,” which,
by activating neighboring sodium channels, can propagate meters away the information that
8
1 Membrane Proteins and Their Natural Environment