Permeability of small nonelectrolytes through lipid bilayer membranes

Anne Walter, John Gutknecht

Diffusion of small nonelectrolytes through planar lipid bilayer membranes (egg phosphatidylcholine-decane) was examined by correlating the permeability coefficients of 22 solutes with their partition coefficients between water and four organic solvents. High correlations were observed with hexadecane and olive oil (r = 0.95 and 0.93), but not octanol and ether (r = 0.75 and 0.74). Permeabilities of the seven smallest molecules (mol wt less than 50) (water, hydrofluoric acid, hydrochloric acid, ammonia, methylamine, formic acid and formamide) were 2- to 15-fold higher than the values predicted by the permeabilities of the larger molecules (50 less than mol wt less than 300). The "extra" permeabilities of the seven smallest molecules were not correlated with partition coefficients but were inversely correlated with molecular volumes. The larger solute permeabilities also decreased with increasing molecular volume, but the relationship was neither steep nor significant. The permeability pattern cannot be explained by the molecular volume dependence of partitioning into the bilayer or by the existence of transient aqueous pores. The molecular volume dependence of solute permeability suggests that the membrane barrier behaves more like a polymer than a liquid hydrocarbon. All the data are consistent with the "solubility-diffusion" model, which can explain both the hydrophobicity dependence and the molecular volume dependence of nonelectrolyte permeability.