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Atomic-Scale Structure and Electrostatics of Anionic Palmitoyloleoylphosphatidylglycerol Lipid Bilayers with Na⁺ Counterions

Wei Zhao ^*, Tomasz Róg ^* , Andrey A. Gurtovenko , Ilpo Vattulainen  ^¶ || and Mikko Karttunen ^**

^* Biophysics and Statistical Mechanics Group, Laboratory of Computational Engineering; Laboratory of Physics and Helsinki Institute of Physics, Helsinki University of Technology, Espoo, Finland; Department of Biophysics, Jagiellonian University, Kraków, Poland; Computational Laboratory, Institute of Pharmaceutical Innovation, University of Bradford, Bradford, West Yorkshire, United Kingdom; ^¶ Institute of Physics, Tampere University of Technology, Tampere, Finland; ^|| MEMPHYS–Center for Biomembrane Physics, University of Southern Denmark, Odense, Denmark; and ^** Department of Applied Mathematics, The University of Western Ontario, London, Ontario, Canada

Correspondence: Address reprint requests to Mikko Karttunen, E-mail: mkarttu{at}uwo.ca; Web: www.softsimu.org.

Anionic palmitoyloleoylphosphatidylglycerol (POPG) is one of the most abundant lipids in nature, yet its atomic-scale properties have not received significant attention. Here we report extensive 150-ns molecular dynamics simulations of a pure POPG lipid membrane with sodium counterions. It turns out that the average area per lipid of the POPG bilayer under physiological conditions is 19% smaller than that of a bilayer built from its zwitterionic phosphatidylcholine analog, palmitoyloleoylphosphatidylcholine. This suggests that there are strong attractive interactions between anionic POPG lipids, which overcome the electrostatic repulsion between negative charges of PG headgroups. We demonstrate that interlipid counterion bridges and strong intra- and intermolecular hydrogen bonding play a key role in this seemingly counterintuitive behavior. In particular, the substantial strength and stability of ion-mediated binding between anionic lipid headgroups leads to complexation of PG molecules and ions and formation of large PG-ion clusters that act in a concerted manner. The ion-mediated binding seems to provide a possible molecular-level explanation for the low permeability of PG-containing bacterial membranes to organic solvents: highly polar interactions at the water/membrane interface are able to create a high free energy barrier for hydrophobic molecules such as benzene.