Abstract
We performed all-atom and coarse-grained simulations of lipid bilayers mixtures of the unsaturated lipid DOPC, with saturated lipids having the same 18-carbon acyl tails and different headgroups, to understand their mechanical properties. The secondary lipids were DSPG, DSPA, DSPS, DSPC and DSPE. The DOPC:DSPG system with 65:35 molar ratio was the softest, with area compressibility modulus KA ~22% smaller than the pure DOPC value. Raising the mole% of DOPC leads to increases in KA, yet at any given composition the KA trend is DSPG < DSPA < DSPS < DSPC < DSPE. Lipid-lipid interactions are weaker in DOPC:DSPG mixtures and stronger in DSPE systems. The head and phosphate groups of the secondary lipids DSPG, DSPA and DSPS interact strongly with salt ions. Adding secondary lipids lead to DOPC having more ordered acyl tails relative to pure DOPC systems. No evidence of phase separation or inhomogeneities was observed in our simulations. We synthesized three liposomal formulations, L-DOPC (pure DOPC), and L-DOPC/DSPG and L-DOPC/DSPA, both with 15 mol% of secondary lipid. L-DOPC/DSPA had approximately 3- and 2-times higher in vitro internalization by normal epithelial (EpH4-Ev) and metastatic breast cancer (4T1) cells, compared with L-DOPC. The uptake of L-DOPC/DSPG by EpH4-Ev cells was almost 2-fold compared to L-DOPC, but both liposomes had similar uptakes by cancer cells. As L-DOPC/DSPG and L-DOPC/DSPA have similar KA values, we presumed that the mechanical properties, possibly in combination with higher negative surface charges in L-DOPC/DSPA and differences in effective liposome diameters and diffusivities, contributed to these observations.
Supplementary materials
Title
Supporting Information
Description
Details of model systems (Table S1); numerical values for area compressibility modulus, lipid-lipid partial and total interaction energies, interaction energies between head and phosphate groups of secondary lipids with salt ions, from all-atom simulations (Tables S2-S5); coarse-grained simulation results for mean and median Voronoi cell areas, percentage of mixed contacts and number and type of neighboring lipids (Tables S6-S10); area per lipid results (Figure S1); order parameter plots (Figures S2-S4); probability histograms of distances between P atoms of secondary lipids (Figures S5-S7); histograms of Voronoi cell areas (Figure S8).
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