The relationship between permeant size and permeability in lipid bilayer membranes

Permeability coefficients (Pm) across planar egg lecithin/decane bilayers and bulk hydrocarbon/water partition coefficients (Kw-->hc) have been measured for 24 solutes with molecular volumes, V, varying by a factor of 22 and Pm values varying by a factor of 10(7) to explore the chemical nature of the bilayer barrier and the effects of permeant size on permeability. A proper bulk solvent which correctly mimics the microenvironment of the barrier domain was sought. Changes in Pm/Kw-->hc were then ascribed to size-dependent partitioning and/or size-dependent diffusivity. The diffusion coefficient-size dependency was described by Dbarrier = Do/Vn. When n-decane was used as a reference solvent, the correlation between log Pm/Kw-->hc and log V was poor (r = 0.56) with most of the lipophilic (hydrophilic) permeants lying below (above) the regression line. Correlations improved significantly (r = 0.87 and 0.90, respectively) with more polarizable solvents, 1-hexadecene and 1,9-decadiene. Values of the size selectivity parameter n were sensitive to the reference solvent (n = 0.8 +/- 0.3, 1.2 +/- 0.1 and 1.4 +/- 0.2, respectively, for decane, hexadecene, and decadiene). Decadiene was selected as the most suitable reference solvent. The value for n in bilayer transport is higher than that for bulk diffusion in decane (n = 0.74 +/- 0.10), confirming the steep dependence of bilayer permeability on molecular size. Statistical mechanical theory recently developed by the authors suggests that a component of this steep size dependence may reside in size-dependent solute partitioning into the ordered chain region of bilayers. This theory, combined with the above diffusion model, yielded the relationship, Pm/Kw-->hc = D(o)exp(-alpha V)Vn. A fit of the experimental data to this model gave the best fit (r = 0.93) with alpha = 0.0053 +/- 0.0021 and n = 0.8 +/- 0.3, suggesting that both diffusion and partitioning mechanisms may play a role in determining the size dependence of lipid bilayer permeabilities.