Effects of Ether Linkage on Membrane Dipole Potential and Cholesterol Flip-Flop Motion in Lipid Bilayer Membranes.

In our previous work, we investigated the effect of ether linkage on the physical properties of lipid bilayers using all-atom (AA) simulations with different water models. However, the influence of ether linkage on the transportation of cholesterol in lipid bilayers is less well studied. In order to reduce computational costs in simulations at large time and length scales, we present coarse-grained (CG) simulations of diphytanyl phosphatidylcholine (ether-DPhPC) and diphytanoyl phosphatidylcholine (ester-DPhPC) bilayer membranes in this work. First, the CG and AA simulations consistently show that the substitution of ether linkage for ester linkage would prevent the penetration of water into the lipid bilayer membranes. Second, it is encouraging that the CG simulations can nicely capture the ether effect on membrane dipole potential, showing that the ether substitution for ester would significantly decrease the dipole potential. In particular, the CG results agree with the AA simulation results, revealing that the change in the dipole potential is accompanied with the alteration in the orientation of linkage group. Finally, we carried out 60 μs CG simulations of ether-DPhPC and ester-DPhPC bilayers at two cholesterol concentrations (10 and 40% mole fraction, respectively), showing that the ether substitution for ester would facilitate the cholesterol flip-flop motion in lipid bilayer membranes.