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

Abstract

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, Ac, 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 Ac,0 = 17.1 Å(2), substantially less than one would estimate by dividing the accepted value A0 = 40.8 Å(2) 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, r(2) = 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.

Composition Dependence of Water Permeation Across Multicomponent Gel-Phase Bilayers

“…The headgroup size largely determines the APL of pure phospholipid bilayers in the gel phase because the projected headgroup area is larger than the combined cross-sectional area of the two acyl tails. 9 This mismatch between cross sections is compensated for by a collective tilt of the lipid tails with respect to the transmembrane axis, thus increasing the packing density of the tails. The APT found for the pure DSPC bilayer is 20.2 Å 2 , in good agreement with the 19.8 Å 2 found via X-ray diffraction.…”

“…For example, it has been suggested that the barrier domain is located deeper in fluidlike phospholipid bilayers than in gel-phase bilayers. 9 This is based upon the idea that for fluidlike bilayers the area occupied by the lipid tails exceeds the projected headgroup area and thus provides space for water molecules to be able to freely move between the lipid headgroups; in contrast, gel-phase systems tend to have densely packed headgroups, which limits the water mobility at the interface. 10 It is also known that the diffusion coefficient of water in a fluidlike bilayer interior is similar to that of bulk water, 11 whereas water diffusion in gel-phase bilayers is typically 2 orders of magnitude smaller than in bulk.…”

“…Permeation is essential to the regulating function of biological systems, such as the bilayers found in cell membranes, including the blood–brain barrier, and the lamellar lipid structures found in the skin. , Whereas the permeability of fluidlike (i.e., liquid-crystalline) bilayers has been actively studied, − little work has focused on dense gel-phase mixtures, for which the permeability is likely to be dictated by different mechanisms than for fluidlike bilayers. For example, it has been suggested that the barrier domain is located deeper in fluidlike phospholipid bilayers than in gel-phase bilayers . This is based upon the idea that for fluidlike bilayers the area occupied by the lipid tails exceeds the projected headgroup area and thus provides space for water molecules to be able to freely move between the lipid headgroups; in contrast, gel-phase systems tend to have densely packed headgroups, which limits the water mobility at the interface .…”

Physics-Based Method for Modeling Passive Membrane Permeability and Translocation Pathways of Bioactive Molecules

“…20–24 Some models, such as the MI-QSAR models developed by Hopfinger, complement properties of solutes by descriptors for membrane interactions calculated by MD simulations. 25 More general QSPR models 26–28 predict partition and permeability coefficients of solutes using a set of five Abraham solvation parameters.…”

Fifty-Eight Years and Counting: High-Impact Publishing in Computational Pharmaceutical Sciences and Mechanism-Based Modeling

“…Tejwani et al 73 addressed the functional group dependence of solute partitioning within 1,2-dioleoyl-snglycero-3-phosphocholine bilayers using molecular dynamic simulations. The very recent work of Nitsche and Kasting 74 addressed the correlation between permeability coefficients of phospholipidcholesterol bilayers and basic chemical properties of dissolving solutes. Research in this area continues today as demonstrated in this special issue.…”