Phospholipids and Glycolipids Readily Form Bimolecular Sheets in Aqueous Media

I. The Molecular Design of Life
12. Lipids and Cell Membranes
12.4. Phospholipids and Glycolipids Readily Form Bimolecular Sheets in Aqueous
Media
What properties enable phospholipids to form membranes? Membrane formation is a consequence of the amphipathic
nature of the molecules. Their polar head groups favor contact with water, whereas their hydrocarbon tails interact with
one another, in preference to water. How can molecules with these preferences arrange themselves in aqueous solutions?
One way is to form a micelle, a globular structure in which polar head groups are surrounded by water and hydrocarbon
tails are sequestered inside, interacting with one another (Figure 12.9).
Alternatively, the strongly opposed preferences of the hydrophilic and hydrophobic moieties of membrane lipids can be
satisfied by forming a lipid bilayer, composed of two lipid sheets (Figure 12.10). A lipid bilayer is also called a
bimolecular sheet. The hydrophobic tails of each individual sheet interact with one another, forming a hydrophobic
interior that acts as a permeability barrier. The hydrophilic head groups interact with the aqueous medium on each side
of the bilayer. The two opposing sheets are called leaflets.
The favored structure for most phospholipids and glycolipids in aqueous media is a bimolecular sheet rather than a
micelle. The reason is that the two fatty acyl chains of a phospholipid or a glycolipid are too bulky to fit into the interior
of a micelle. In contrast, salts of fatty acids (such as sodium palmitate, a constituent of soap), which contain only one
chain, readily form micelles. The formation of bilayers instead of micelles by phospholipids is of critical biological
importance. A micelle is a limited structure, usually less than 20 nm (200 Å) in diameter. In contrast, a bimolecular sheet
can have macroscopic dimensions, such as a millimeter (106 nm, or 107 Å). Phospholipids and related molecules are
important membrane constituents because they readily form extensive bimolecular sheets (Figure 12.11).
The formation of lipid bilayers is a self-assembly process. In other words, the structure of a bimolecular sheet is inherent
in the structure of the constituent lipid molecules. The growth of lipid bilayers from phospholipids is a rapid and
spontaneous process in water. Hydrophobic interactions are the major driving force for the formation of lipid bilayers.
Recall that hydrophobic interactions also play a dominant role in the folding of proteins (Sections 1.3.4 and 3.4) and in
the stacking of bases in nucleic acids (Section 5.2.1). Water molecules are released from the hydrocarbon tails of
membrane lipids as these tails become sequestered in the nonpolar interior of the bilayer. Furthermore, van der Waals
attractive forces between the hydrocarbon tails favor close packing of the tails. Finally, there are electrostatic and
hydrogen-bonding attractions between the polar head groups and water molecules. Thus, lipid bilayers are stabilized by
the full array of forces that mediate molecular interactions in biological systems.
Because lipid bilayers are held together by many reinforcing, noncovalent interactions (predominantly hydrophobic),
they are cooperative structures. These hydrophobic interactions have three significant biological consequences: (1) lipid
bilayers have an inherent tendency to be extensive; (2) lipid bilayers will tend to close on themselves so that there are no
edges with exposed hydrocarbon chains, and so they form compartments; and (3) lipid bilayers are self-sealing because a
hole in a bilayer is energetically unfavorable.
12.4.1. Lipid Vesicles Can Be Formed from Phospholipids
The propensity of phospholipids to form membranes has been used to create an important experimental and clinical tool.
Lipid vesicles, or liposomes, aqueous compartments enclosed by a lipid bilayer (Figure 12.12), can be used to study
membrane permeability or to deliver chemicals to cells. Liposomes are formed by suspending a suitable lipid, such as
phosphatidyl choline, in an aqueous medium, and then sonicating (i.e., agitating by high-frequency sound waves) to give
a dispersion of closed vesicles that are quite uniform in size. Vesicles formed by these methods are nearly spherical in
shape and have a diameter of about 50 nm (500 Å). Larger vesicles (of the order of 1 µm, or 104 Å, in diameter) can be
prepared by slowly evaporating the organic solvent from a suspension of phospholipid in a mixed solvent system.
Ions or molecules can be trapped in the aqueous compartments of lipid vesicles by forming the vesicles in the presence
of these substances (Figure 12.13). For example, 50-nm-diameter vesicles formed in a 0.1 M glycine solution will trap
about 2000 molecules of glycine in each inner aqueous compartment. These glycine-containing vesicles can be separated
from the surrounding solution of glycine by dialysis or by gel-filtration chromatography (Section 4.1.3). The
permeability of the bilayer membrane to glycine can then be determined by measuring the rate of efflux of glycine from
the inner compartment of the vesicle to the ambient solution. Specific membrane proteins can be solubilized in the
presence of detergents and then added to the phospholipids from which liposomes will be formed. Protein-liposome
complexes provide valuable experimental tools for examining a range of membrane-protein functions.
Experiments are underway to develop clinical uses for liposomes. For example, liposomes containing drugs or
DNA for gene-therapy experiments can be injected into patients. These liposomes fuse with the plasma membrane
of many kinds of cells, introducing into the cells the molecules that they contain. Drug delivery with liposomes also
alters the distribution of a drug within the body and often lessens its toxicity. For instance, less of the drug is distributed
to normal tissues because longcirculating liposomes have been shown to concentrate in regions of increased blood
circulation, such as solid tumors and sites of inflammation. Moreover, the selective fusion of lipid vesicles with
particular kinds of cells is a promising means of controlling the delivery of drugs to target cells.
Another well-defined synthetic membrane is a planar bilayer membrane. This structure can be formed across a 1-mm
hole in a partition between two aqueous compartments by dipping a fine paintbrush into a membrane-forming solution,
such as phosphatidyl choline in decane. The tip of the brush is then stroked across a hole (1 mm in diameter) in a
partition between two aqueous media. The lipid film across the hole thins spontaneously into a lipid bilayer. The
electrical conduction properties of this macroscopic bilayer membrane are readily studied by inserting electrodes into
each aqueous compartment (Figure 12.14). For example, its permeability to ions is determined by measuring the current
across the membrane as a function of the applied voltage.
12.4.2. Lipid Bilayers Are Highly Impermeable to Ions and Most Polar Molecules
The results of permeability studies of lipid vesicles and electrical-conductance measurements of planar bilayers have
shown that lipid bilayer membranes have a very low permeability for ions and most polar molecules. Water is a
conspicuous exception to this generalization; it readily traverses such membranes because of its small size, high
concentration, and lack of a complete charge. The range of measured permeability coefficients is very wide (Figure
12.15). For example, Na+ and K+ traverse these membranes 109 times as slowly as does H2O. Tryptophan, a zwitterion
at pH 7, crosses the membrane 103 times as slowly as does indole, a structurally related molecule that lacks ionic groups.
In fact, the permeability coefficients of small molecules are correlated with their solubility in a nonpolar solvent relative
to their solubility in water. This relation suggests that a small molecule might traverse a lipid bilayer membrane in the
following way: first, it sheds its solvation shell of water; then, it becomes dissolved in the hydrocarbon core of the
membrane; finally, it diffuses through this core to the other side of the membrane, where it becomes resolvated by water.
An ion such as Na+ tra-verses membranes very slowly because the replacement of its coordination shell of polar water
molecules by nonpolar interactions with the membrane interior is highly unfavorable energetically.
I. The Molecular Design of Life
12. Lipids and Cell Membranes
12.4. Phospholipids and Glycolipids Readily Form Bimolecular Sheets in Aqueous Media
Figure 12.9. Diagram of a Section of a Micelle. Ionized fatty acids readily form such structures, but most
phospholipids do not.
I. The Molecular Design of Life
12. Lipids and Cell Membranes
12.4. Phospholipids and Glycolipids Readily Form Bimolecular Sheets in Aqueous Media
Figure 12.10. Diagram of a Section of a Bilayer Membrane.
I. The Molecular Design of Life
12. Lipids and Cell Membranes
12.4. Phospholipids and Glycolipids Readily Form Bimolecular Sheets in Aqueous Media
Figure 12.11. Space-Filling Model of a Section of Phospholipid Bilayer Membrane.
I. The Molecular Design of Life
12. Lipids and Cell Membranes
12.4. Phospholipids and Glycolipids Readily Form Bimolecular Sheets in Aqueous Media
Figure 12.12. Liposome. A liposome, or lipid vesicle, is a small aqueous compartment surrounded by a lipid bilayer.
I. The Molecular Design of Life
12. Lipids and Cell Membranes
12.4. Phospholipids and Glycolipids Readily Form Bimolecular Sheets in Aqueous Media
Figure 12.13. Preparation of Glycine-Containing Liposome. Liposomes containing glycine are formed by sonication
of phospholipids in the presence of glycine. Free glycine is removed by gel filtration.
I. The Molecular Design of Life
12. Lipids and Cell Membranes
12.4. Phospholipids and Glycolipids Readily Form Bimolecular Sheets in Aqueous Media
Figure 12.14. Experimental Arrangement for the Study of Planar Bilayer Membrane. A bilayer membrane is
formed across a 1-mm hole in a septum that separates two aqueous compartments. This arrangement permits
measurements of the permeability and electrical conductance of lipid bilayers.