The Structure of Lipids and Biological Membranes

Lipids are defined not by a shared functional group, as amino acids and carbohydrates are, but by a shared physical property: insolubility in water and solubility in nonpolar organic solvents. This chapter surveys the structural chemistry of the major lipid classes — fatty acids, triacylglycerols, glycerophospholipids and sphingolipids, and cholesterol — before using their amphipathic chemistry to build the fluid mosaic model of the biological membrane, the structure that separates every cell, and every membrane-bound organelle within it, from its surroundings.

This chapter deliberately stops at membrane structure; membrane transport (channels, carriers, pumps) belongs to a dedicated physiology treatment, and the catabolism of fatty acids is developed later in this block (Chapter 9), once the glycolytic and respiratory machinery of Chapters 7–8 is in place. What matters here is the direct, causal link between a lipid's molecular shape and the architecture it assembles into.

1. Fatty Acids

A fatty acid is a long, unbranched hydrocarbon chain terminating in a carboxyl group, typically 12–24 carbons long in biological systems. Two properties classify any fatty acid:

Saturation. A saturated fatty acid has no carbon–carbon double bonds; every carbon is "saturated" with hydrogen. An unsaturated fatty acid has one or more C=C double bonds, almost always in the cis configuration in naturally occurring lipids. A monounsaturated fatty acid has exactly one double bond; a polyunsaturated fatty acid has two or more.
Chain length and numbering. Carbons are numbered from the carboxyl carbon (C1); the position of a double bond is given either by this numbering ( $\Delta^9$ meaning a double bond starting at C9) or by counting from the opposite, methyl end ( $\omega$ , omega) — the origin of the term "omega-3 fatty acid" for a double bond beginning at the third carbon from the methyl end.

Key distinction. A cis double bond introduces a rigid ~ $30^\circ$ kink into an otherwise straight hydrocarbon chain, preventing the tight, regular packing that saturated chains achieve. This single structural fact explains why unsaturated fats are liquid (oils) at room temperature while saturated fats are solid, and — developed further in Section 5 — why unsaturated fatty acid content increases membrane fluidity.

Worked example. Palmitic acid, a saturated fatty acid, has 16 carbons and melts at $63\,^\circ\text{C}$ . Oleic acid, an 18-carbon monounsaturated fatty acid with a single cis double bond at $\Delta^9$ , melts at $13\,^\circ\text{C}$ — despite having more carbons, and therefore more van der Waals contact area available, than palmitic acid. The kink introduced by the single cis double bond disrupts packing efficiently enough to overwhelm the extra two carbons' worth of van der Waals attraction, lowering the melting point by $50\,^\circ\text{C}$ .

2. Triacylglycerols

A triacylglycerol (or triglyceride) is formed by esterifying all three hydroxyl groups of glycerol (propane-1,2,3-triol) with three fatty acids, releasing three molecules of water:

\text{glycerol} + 3\ \text{fatty acid} \ \longrightarrow\ \text{triacylglycerol} + 3\text{H}_2\text{O}

The three fatty acid chains may be identical or different. Because triacylglycerols carry no charged or strongly polar head group, they are the most nonpolar of the major lipid classes and are stored, essentially anhydrous, in specialised cells (adipocytes) as the body's principal long-term energy reserve. This is a direct structural contrast with the polysaccharide energy store glycogen (Chapter 3): glycogen's many polar hydroxyl groups bind substantial water, giving it a far lower energy density per gram of hydrated tissue mass than triacylglycerol's essentially water-free storage — a comparison made quantitative in Chapter 9.

3. Glycerophospholipids

A glycerophospholipid replaces one of a triacylglycerol's three fatty acids with a phosphate group, itself typically esterified to a small polar or charged head group (e.g. choline, ethanolamine, serine):

\underset{\text{glycerol backbone}}{\text{C1, C2: fatty acid esters}} \quad \underset{\text{C3}}{\text{phosphate} - \text{head group}}

This architecture — two long, nonpolar fatty acid "tails" at C1 and C2, and one charged or polar phosphate–head group "head" at C3 — makes a glycerophospholipid amphipathic: possessing both a hydrophilic region and a hydrophobic region within a single molecule.

Definition. An amphipathic (or amphiphilic) molecule has spatially distinct hydrophilic and hydrophobic regions. Placed in water, such molecules spontaneously self-assemble to minimise unfavourable contact between the hydrophobic tails and water — the same hydrophobic-effect thermodynamics (favourable solvent entropy) that drove tertiary protein folding in Chapter 1.

Common glycerophospholipids are named for their head group: phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol. Phosphatidylserine's head group carries a net negative charge and is normally confined to the cytosolic (inner) leaflet of the plasma membrane; its appearance on the outer leaflet is a well-characterised signal for recognition and clearance of apoptotic (programmed cell death) cells.

4. Sphingolipids

Sphingolipids are built not on a glycerol backbone but on sphingosine, a long-chain amino alcohol. A fatty acid is attached via an amide bond to sphingosine's amino group to form ceramide, the structural parent of every sphingolipid:

Sphingomyelin: ceramide with a phosphocholine or phosphoethanolamine head group — structurally a phospholipid in function (hence its inclusion among the "membrane phospholipids"), despite its sphingosine rather than glycerol backbone. Abundant in the myelin sheath insulating nerve axons.
Glycosphingolipids (cerebrosides, gangliosides): ceramide with one or more sugar residues attached directly (via a glycosidic bond, Chapter 3) in place of a phosphate head group. Found predominantly in the outer leaflet of the plasma membrane, with their sugar head groups facing the extracellular space — a direct structural basis for the carbohydrate-mediated molecular recognition introduced in the previous chapter, including the ABO blood group antigens.

5. Cholesterol and Membrane Fluidity

Cholesterol is a steroid: a lipid built on a rigid, fused four-ring (three six-membered, one five-membered) hydrocarbon skeleton, with a single hydroxyl group at C3 and a short hydrocarbon tail. It is amphipathic, though only weakly so: its single hydroxyl is a far smaller polar region than a phospholipid's phosphate head group, while its rigid ring system is strongly hydrophobic.

Embedded within the membrane, cholesterol's rigid rings intercalate between the fatty acid tails of neighbouring phospholipids, producing an effect dependent on temperature:

Above the membrane's transition temperature (physiological conditions for most mammalian cells), cholesterol restrains local phospholipid motion, decreasing fluidity, by restricting the tails' conformational freedom.
Below the transition temperature, cholesterol increases fluidity, by preventing the fatty acid tails from packing into the fully ordered, crystalline arrangement that would otherwise cause the membrane to solidify.

Cholesterol is therefore best described as a fluidity buffer, moderating the membrane's fluidity in both directions and narrowing the sharp phase transition that a pure phospholipid bilayer would otherwise undergo at a single, specific temperature.

6. Membrane Self-Assembly: Bilayers and Micelles

When amphipathic lipids are dispersed in water, the hydrophobic effect drives them to self-assemble into one of several characteristic structures, determined chiefly by molecular shape:

Micelles: a single layer of lipid molecules with tails pointing inward (shielded from water) and heads pointing outward, favoured by molecules with a single tail and a relatively large head group (an overall cone shape), such as free fatty acids and detergents.
Bilayers: two layers (leaflets) of lipid arranged tail-to-tail, with both sets of head groups facing outward into the aqueous environment on either side. Favoured by molecules with roughly cylindrical overall shape — two tails and a head group of comparable cross-sectional area — exactly the geometry of a typical glycerophospholipid.

A bilayer formed this way can close on itself into a sealed, spherical liposome, eliminating all exposed hydrophobic edge — the thermodynamically most stable arrangement for bilayer-forming lipids in water, and the structural basis of every biological membrane.

Worked example. A phospholipid bilayer is approximately $4~\text{nm}$ thick. Estimate the number of bilayers that would fit across a typical animal cell diameter of $20~\mu\text{m}$ , if (hypothetically) stacked edge to edge.

Converting to consistent units, $20~\mu\text{m} = 2.0\times 10^{4}~\text{nm}$ :

\text{number of bilayers} = \frac{2.0\times 10^{4}~\text{nm}}{4~\text{nm}} = 5.0\times 10^{3}

This illustrates the vast scale mismatch between a cell's overall dimensions and the nanometre-scale thinness of the single membrane that defines its boundary.

7. The Fluid Mosaic Model

The modern description of membrane structure, proposed by Singer and Nicolson in 1972, is the fluid mosaic model:

Definition. The fluid mosaic model describes the biological membrane as a two-dimensional fluid in which individual phospholipid molecules, and the proteins embedded within or attached to them, diffuse laterally — a "mosaic" of varied protein and lipid components set within a "fluid" lipid bilayer, rather than a rigid, fixed structure.

Two broad classes of membrane protein are distinguished by how they associate with the bilayer:

Integral membrane proteins span, or are permanently embedded within, the hydrophobic core of the bilayer, typically via one or more $\alpha$ -helical transmembrane segments (recall from Chapter 1 that a transmembrane $\alpha$ -helix of roughly 20 residues spans the $\sim 30~\text{\AA}$ hydrophobic core of a typical bilayer). Removing an integral protein from the membrane requires disrupting the bilayer itself, e.g. with a detergent.
Peripheral membrane proteins associate with the membrane surface or with an integral protein, through non-covalent interactions (ionic, hydrogen bonding) rather than by penetrating the hydrophobic core, and can typically be removed by gentler treatments, such as a change in pH or ionic strength.

Membrane lipid composition is also asymmetric between the two leaflets: phosphatidylcholine and sphingomyelin are enriched in the outer leaflet, phosphatidylserine and phosphatidylethanolamine in the inner (cytosolic) leaflet, and glycolipids are found almost exclusively in the outer leaflet, consistent with their role in extracellular molecular recognition (Section 4). This asymmetry is established and actively maintained by specific transport enzymes (flippases, floppases), developed no further here.

8. Common Exam Pitfalls

Treating "lipid" as a structurally defined class, like "amino acid" or "monosaccharide." Lipids are unified only by a shared solubility property (hydrophobicity), not by a shared functional group; fatty acids, triacylglycerols, phospholipids, sphingolipids and cholesterol are all structurally distinct.
Assuming all unsaturated fatty acid double bonds are trans. Naturally occurring unsaturated fatty acids are overwhelmingly cis; trans fats are predominantly an artefact of industrial partial hydrogenation, and pack far more like saturated fatty acids as a direct consequence of their straighter chain shape.
Confusing a glycerophospholipid's structure with a triacylglycerol's. A triacylglycerol has three fatty acid esters and no phosphate; a glycerophospholipid has only two fatty acid esters, with the third glycerol position occupied by a phosphate–head group — a change of just one substituent with major functional consequences (nonpolar storage lipid versus amphipathic membrane lipid).
Forgetting that sphingolipids use a different backbone from glycerophospholipids. Sphingomyelin and the glycosphingolipids are built on sphingosine, not glycerol; the shared vocabulary of "head group" and "tail" can obscure this structural difference if not stated explicitly.
Treating cholesterol's fluidity effect as one-directional. Cholesterol's effect depends on temperature relative to the membrane's transition temperature: it decreases fluidity above that temperature and increases it below — "fluidity buffer" is the precise, bidirectional description, not simply "decreases fluidity."
Describing the fluid mosaic model as a static structure. The defining feature of the model is lateral fluidity — continuous diffusion of lipids and many proteins within the plane of the membrane — not a fixed arrangement of components.

Summary

Fatty acids are classified by saturation (number of C=C double bonds, almost always cis) and chain length; cis double bonds introduce packing-disrupting kinks that lower melting point and, in a membrane, increase fluidity.
Triacylglycerols (glycerol + 3 fatty acids, fully esterified) are nonpolar, anhydrous energy stores; glycerophospholipids (glycerol + 2 fatty acids + a phosphate–head group) are amphipathic membrane components.
Sphingolipids (sphingomyelin, glycosphingolipids) are built on the amino alcohol sphingosine via the parent compound ceramide, not on glycerol.
Cholesterol, a steroid, acts as a bidirectional fluidity buffer: it decreases membrane fluidity above the transition temperature and increases it below.
Amphipathic lipids self-assemble in water, driven by the hydrophobic effect, into micelles (cone-shaped molecules) or bilayers (cylindrical molecules, e.g. phospholipids), which can close into sealed liposomes.
The fluid mosaic model (Singer–Nicolson) describes the membrane as a laterally fluid lipid bilayer embedding integral (bilayer-spanning) and peripheral (surface-associated) proteins, with compositionally asymmetric leaflets.
The next chapter turns to nucleic acids, where the same amphipathic logic resurfaces briefly in the context of the sugar–phosphate backbone's own strongly hydrophilic character.