Local Partition Coefficients Govern Solute Permeability of Cholesterol-Containing Membranes

Abstract

The permeability of lipid membranes for metabolic molecules or drugs is routinely estimated from the solute's oil/water partition coefficient. However, the molecular determinants that modulate the permeability in different lipid compositions have remained unclear. Here, we combine scanning electrochemical microscopy and molecular-dynamics simulations to study the effect of cholesterol on membrane permeability, because cholesterol is abundant in all animal membranes. The permeability of membranes from natural lipid mixtures to both hydrophilic and hydrophobic solutes monotonously decreases with cholesterol concentration [Chol]. The same is true for hydrophilic solutes and planar bilayers composed of dioleoyl-phosphatidylcholine or dioleoyl-phosphatidyl-ethanolamine. However, these synthetic lipids give rise to a bell-shaped dependence of membrane permeability on [Chol] for very hydrophobic solutes. The simulations indicate that cholesterol does not affect the diffusion constant inside the membrane. Instead, local partition coefficients at the lipid headgroups and at the lipid tails are modulated oppositely by cholesterol, explaining the experimental findings. Structurally, these modulations are induced by looser packing at the lipid headgroups and tighter packing at the tails upon the addition of cholesterol.

Low levels of lipid oxidation radically increase the passive permeability of lipid bilayers

“…Finally, cholesterol was added to increase membrane permeability, making the transport process sufficiently slow to measure precisely. 27 The amount of cholesterol was tailored such that GUVs containing POxnoPC did not show phase separation in fluorescent microscopy of the labeled GUV membrane. Prior to every transport experiment, we verified that no phase separation was apparent in the membrane of the selected GUV.…”

Shedding light on the puzzle of drug-membrane interactions: Experimental techniques and molecular dynamics simulations

“…Using MD simulations, Zocher et al (2013) showed that cholesterol can influence the local partition coefficients at the lipid headgroups and at the lipid tails in different manners [27]. This can be attributed to by the contrary effect that cholesterol has on lipid packing in both regions, namely, it decreases the packing at the lipid headgroups and increases the packing at the hydrophobic tails [27]. Additionally, Wennberg et al [29].…”

“…Experimentally, it was already proven that the presence of cholesterol reduces the solute partition coefficients due to its intercalation between the hydrophobic chains of phospholipids, which increases their packing [250]. Using MD simulations, Zocher et al (2013) showed that cholesterol can influence the local partition coefficients at the lipid headgroups and at the lipid tails in different manners [27]. This can be attributed to by the contrary effect that cholesterol has on lipid packing in both regions, namely, it decreases the packing at the lipid headgroups and increases the packing at the hydrophobic tails [27].…”

Effect of Cholesterol on the Interaction of Cytochrome P450 Substrate Drug Chlorzoxazone with the Phosphatidylcholine Bilayer

“…This supports a previous prediction from a computational study on drug permeability using other model drug-membrane system. 30 The 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 24…”