A Universal Correlation Predicts Permeability Coefficients of Fluid- and Gel-Phase Phospholipid and Phospholipid-Cholesterol Bilayers for Arbitrary Solutes

The permeability of gel-phase phospholipids is typically about an order of magnitude lower than that of the same compositions in the fluid phase, yet a quantitative description of the ordering factors leading to this difference has been elusive. The present analysis examines these factors with particular focus on the area per phospholipid chain, A_c, and its relationship to the minimum area per molecule in the crystalline state, A₀. It is shown that fluid- and gel-phase phospholipid permeabilities can be reconciled by postulating a minimum area per chain A_c,0 = 17.1 Ų, substantially less than one would estimate by dividing the accepted value A₀ = 40.8 Ų by 2. An extended data set of phospholipid and phospholipid-cholesterol bilayer permeability data extending over 9 orders of magnitude is analyzed and correlated according to the developed relationship (N = 85, s = 0.3024, r² = 0.9332). Individual permeability values are consequently predicted to within an average deviation of 10^0.3024 or about a factor of 2. The analysis is broadly applicable in the fluid phase but is restricted to gel-phase phospholipid compositions that do not contain cholesterol. Guidance for the latter scenario is provided.