Polymer-induced flip-flop in biomembranes

This Account describes the ability of amphiphilic polymers ( e.g., EO/PO/EO block copolymers) and polycations [e.g., quaternized poly(4-vinylpyridine)] to accelerate translocation from the inside leaflet to the outside leaflet (flip-flop) within vesicle bilayer membranes. Driving forces and mechanisms of flip-flop catalyzed by the nonionic and cationic polymers are different. The nonionics are bound to the biological membrane via incorporation of their hydrophobic blocks into the inner part of the lipid bilayer occupied by the hydrocarbon chains. The resulting scrambling of lipid molecules is favored by the overall hydrophobicity of the copolymer and the volume of its hydrophobic block. External binding of the cationic polymers, on the other hand, is driven by electrostatic interactions between the positively charged polymer units and the negatively charged lipid headgroups within the outside leaflet. Electrostatic binding favors both the flip-flop of anionic lipid from the inner to outer leaflet and the formation of anionic domains in the outer leaflet. When it is considered that less than 1% of the liposome surface is occupied by certain bound polymers, their effect upon membrane dynamics, as will be described herein, is considerable. A distinct correlation has been found between the flippase activity of the polymers and their ability to mediate drug permeation through biomembranes.