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Cationic DMPC/DMTAP Lipid Bilayers: Molecular Dynamics Study

Andrey A. Gurtovenko ^* , Michael Patra , Mikko Karttunen  and Ilpo Vattulainen ^*

^* Laboratory of Physics and Helsinki Institute of Physics, Helsinki University of Technology, FIN-02015 HUT, Finland; Institute of Macromolecular Compounds, Russian Academy of Sciences, St. Petersburg, 199004 Russia; and Biophysics and Statistical Mechanics Group, Laboratory of Computational Engineering, Helsinki University of Technology, FIN-02015 HUT, Finland

Correspondence: Address reprint requests to Dr. Andrey A. Gurtovenko, Laboratory of Physics, Helsinki University of Technology, PO Box 1100, FIN-02015 HUT, Finland. Tel.: 358-9-4515803; E-mail: agu{at}fyslab.hut.fi.

Cationic lipid membranes are known to form compact complexes with DNA and to be effective as gene delivery agents both in vitro and in vivo. Here we employ molecular dynamics simulations for a detailed atomistic study of lipid bilayers consisting of a mixture of cationic dimyristoyltrimethylammonium propane (DMTAP) and zwitterionic dimyristoylphosphatidylcholine (DMPC). Our main objective is to examine how the composition of the DMPC/DMTAP bilayers affects their structural and electrostatic properties in the liquid-crystalline phase. By varying the mole fraction of DMTAP, we have found that the area per lipid has a pronounced nonmonotonic dependence on the DMTAP concentration, with a minimum around the point of equimolar DMPC/DMTAP mixture. We show that this behavior has an electrostatic origin and is driven by the interplay between positively charged TAP headgroups and the zwitterionic phosphatidylcholine (PC) heads. This interplay leads to considerable reorientation of PC headgroups for an increasing DMTAP concentration, and gives rise to major changes in the electrostatic properties of the lipid bilayer, including a significant increase of total dipole potential across the bilayer and prominent changes in the ordering of water in the vicinity of the membrane. Moreover, chloride counterions are bound mostly to PC nitrogens implying stronger screening of PC heads by Cl ions compared to TAP headgroups. The implications of these findings are briefly discussed.

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