Structural Determinants of Water Permeability through the Lipid Membrane

TLDR

Despite intense study over many years, the mechanisms by which water and small nonelectrolytes cross lipid bilayers remain unclear. The study examined water permeability in seven single‑component bilayers of varying lipid headgroups and chain properties, and also incorporated cholesterol into DOPC bilayers, using X‑ray diffuse scattering to quantify how cholesterol reduces area per lipid while increasing bilayer thickness without changing lipid volume. Water permeability is most strongly correlated with area per lipid, weakly with bilayer thickness, leading to a new model where lipid area dominates and thickness is secondary; cholesterol addition reduces permeability and alters correlations with area per lipid, thickness, and compressibility.

Abstract

Despite intense study over many years, the mechanisms by which water and small nonelectrolytes cross lipid bilayers remain unclear. While prior studies of permeability through membranes have focused on solute characteristics, such as size, polarity, and partition coefficient in hydrophobic solvent, we focus here on water permeability in seven single component bilayers composed of different lipids, five with phosphatidylcholine headgroups and different chain lengths and unsaturation, one with a phosphatidylserine headgroup, and one with a phosphatidylethanolamine headgroup. We find that water permeability correlates most strongly with the area/lipid and is poorly correlated with bilayer thickness and other previously determined structural and mechanical properties of these single component bilayers. These results suggest a new model for permeability that is developed in the accompanying theoretical paper in which the area occupied by the lipid is the major determinant and the hydrocarbon thickness is a secondary determinant. Cholesterol was also incorporated into DOPC bilayers and X-ray diffuse scattering was used to determine quantitative structure with the result that the area occupied by DOPC in the membrane decreases while bilayer thickness increases in a correlated way because lipid volume does not change. The water permeability decreases with added cholesterol and it correlates in a different way from pure lipids with area per lipid, bilayer thickness, and also with area compressibility.