With its dense hydrophobic core, a phospholipid bilayer is largely impermeable to water-soluble molecules and ions. Only gases, such as O₂ and CO₂, and small uncharged polar molecules, such as urea and ethanol, can readily move across an artificial membrane composed of pure phospholipid or of phospholipid and cholesterol (see Figure 11-1). Such molecules can also diffuse across cellular membranes without the aid of transport proteins. No metabolic energy is expended during simple diffusion because movement is from a high to a low concentration of the molecule, down its chemical concentration gradient. As noted in Chapter 2, such movements are spontaneous because they have a positive ΔS value (increase in entropy) and thus a negative ΔG (decrease in free energy).

The diffusion rate of any substance across a pure phospholipid bilayer is proportional to its concentration gradient across the bilayer and to its hydrophobicity and size; the movement of charged molecules is also affected by any electric potential across the membrane. When a pure phospholipid bilayer separates two aqueous spaces, or “compartments,” membrane permeability can be easily determined by adding a small amount of labeled material to one compartment and measuring its rate of appearance in the other compartment. The label can be radioactive or nonradioactive—for example, a fluorescent label whose light emission can be measured. The greater the concentration gradient of the substance, the faster its rate of movement across a bilayer.

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The hydrophobicity of a substance is determined by measuring its partition coefficient K, the equilibrium constant for its partition between oil and water. The higher a substance’s partition coefficient (the greater the fraction found in oil relative to water), the more lipid soluble it is, and therefore, the faster its rate of movement across a bilayer. The first and rate-limiting step in transport by simple diffusion is movement of a molecule from the aqueous solution into the hydrophobic interior of the phospholipid bilayer, which resembles olive oil in its chemical properties. This is the reason that the more hydrophobic a molecule is, the faster it diffuses across a pure phospholipid bilayer. For example, diethylurea, with an ethyl group attached to each nitrogen atom:

has a K of 0.01, whereas urea

has a K of 0.0002. Diethylurea, which is 50 times (0.01/0.0002) more hydrophobic than urea, will therefore diffuse through a pure phospholipid bilayer about 50 times faster than urea. Similarly, fatty acids with longer hydrocarbon chains are more hydrophobic than those with shorter chains and at all concentrations will diffuse more rapidly across a pure phospholipid bilayer.

If a substance carries a net charge, its movement across a membrane is influenced by both its concentration gradient and the membrane potential, the electric potential (voltage) across the membrane. The combination of these two forces, called the electrochemical gradient, determines the energetically favorable direction of movement of a charged molecule across a membrane. The electric potential that exists across most cellular membranes results from a small imbalance in the concentrations of positively and negatively charged ions on the two sides of the membrane. We discuss how this ionic imbalance, and the resulting potential, arise and are maintained in Sections 11.4 and 11.5.