Abstract
The functional significance of ordered nanodomains (or rafts) in cholesterol rich eukaryotic cell membranes has only begun to be explored. This study exploits the correspondence of cellular rafts and liquid ordered (Lo) phases of three-component lipid bilayers to examine permeability. Molecular dynamics simulations of Lo phase dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylcholine (DOPC), and cholesterol show that oxygen and water transit a leaflet through the DOPC and cholesterol rich boundaries of hexagonally packed DPPC microdomains, freely diffuse along the bilayer midplane, and escape the membrane along the boundary regions. Electron paramagnetic resonance experiments provide critical validation: the measured ratio of oxygen concentrations near the midplanes of liquid disordered (Ld) and Lo bilayers of DPPC/DOPC/cholesterol is 1.75 ± 0.35, in very good agreement with 1.3 ± 0.3 obtained from simulation. The results show how cellular rafts can be structurally rigid signaling platforms while remaining nearly as permeable to small molecules as the Ld phase.
Highlights
The functional significance of ordered nanodomains in cholesterol rich eukaryotic cell membranes has only begun to be explored
As detailed further in the Methods section, the simulated and experimental systems presented here are of homogeneous liquid ordered and liquid disordered phases of DPPC/DOPC/cholesterol; i.e., they are not mixtures of the two phases
The highlighted oxygen enters a region between clusters of hexagonally packed DPPC chains, and rapidly diffuses along this interface to the center of the bilayer, which contains most of the other oxygens
Summary
The functional significance of ordered nanodomains (or rafts) in cholesterol rich eukaryotic cell membranes has only begun to be explored. This study exploits the correspondence of cellular rafts and liquid ordered (Lo) phases of three-component lipid bilayers to examine permeability. Electron paramagnetic resonance experiments provide critical validation: the measured ratio of oxygen concentrations near the midplanes of liquid disordered (Ld) and Lo bilayers of DPPC/DOPC/cholesterol is 1.75 ± 0.35, in very good agreement with 1.3 ± 0.3 obtained from simulation. Oxygen and water are excellent candidates for such a study They are small and their permeation can thereby be simulated directly using conventional MD, as opposed to enhanced sampling methods[10] that are not yet validated for liquid ordered phases. Their hydrophobicities span a wide range that includes many permeants of general interest. Simulations have revealed similar ordered microdomains in Lo phases containing N-palmitoyl sphingomyelin (PSM)[28]
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