Molecular Dynamics Simulation of Inverse-Phosphocholine Lipids

Abstract

We have performed molecular dynamics simulations of lipid bilayers composed of inverse-phosphatidylcholines (CPe), an analog of phosphatidylcholine (PC) with the choline group directly bound to the glycerol backbone and the phosphate group freely protruding into the water phase. Synthetic phospholipids with the CPe headgroup have been proposed for use as drug delivery liposomes. Our simulation results show that the CPe lipids were characterized by a larger area per lipid molecule than the PC lipids. This can partly explain experimental results that show a higher permeability of small solutes through the membranes of liposomes composed of them. Unlike the PC headgroup, the CPe headgroup was found not to bind sodium ions at the water membrane interface. Both lipid types were found to bind calcium ions but do not bind potassium ions. Inversion of the choline group was found to decrease hydration of the membrane in the carbonyl region of the bilayer as well as hydration of the choline group. From analyzing the water ordering in our simulation, we determined that the orientation of the water layer next to the CPe membrane is effectively inverted with respect to the water ordering of the PC membrane, possibly affecting interaction with biomembranes encountered in drug delivery. Due to changes in ion binding, charge group distribution, and water orientation, the electrostatic potential profiles across the lipid bilayer of CPe membranes were found to differ considerably from those of PC membranes. This is a possible explanation of the experimentally observed changes in the charged solute permeability.