Electroporation Sensitivity of Oxidized Phospholipid Bilayers

Abstract

Molecular dynamics (MD) studies showing that oxidized lipids increase the frequency of water defects in phospholipid bilayers suggest that the presence of oxidized lipids in a bilayer will also increase the sensitivity of the bilayer to electropermeabilization. To investigate this possibility we applied external electric fields during MD simulations of PLPC (1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphatidylcholine) bilayers containing varying concentrations of oxidized PLPC species - the peroxidized linoleic acid derivatives 12-oxo-9-dodecenoic acid (12-al), which contains an aldehyde group, and 13-trans, cis-hydroperoxide linoleic acid (13-tc), which contains a hydroperoxide group. Systems with higher concentrations of oxidized lipids form hydrophilic electropores in significantly shorter times than do systems with lower oxidized lipid concentrations, and at lower electric fields. Furthermore, bilayers containing 12-al electroporate more quickly than bilayers containing 13-tc, possibly a result of the decreased thickness of membranes containing 12-al. Sites of water defect formation and subsequent electroporation appear to coincide with local clustering of oxidized lipids in the bilayer. In large-area simulations containing localized high oxidized lipid concentrations, pores formed preferentially in these oxidized regions. The tendency of the oxidized lipids to bend their sn-2 tail toward the aqueous interface, which may result in membrane thinning and a decrease in the lipid areal density, was not noticeably enhanced by the application of an external electric field, but the presence of the aldehyde and hydroperoxy oxygens on the otherwise nonpolar lipid tails appears to facilitate the penetration of water into the bilayer interior. Simulation results were verified by experimental observations of enhanced permeabilization of oxidized membranes in living cells.