Lipid Domains in Zwitterionic-Anionic Lipid Mixtures Induced by Combined Effect of Monovalent and Divalent Ions

Abstract

Membranes are vital components in cellular regulatory system, upon which many metal ion molecules act as messengers of intracellular signaling and mediators for membrane protein association. In particular, anionic lipid phosphatidylserine (PS) is involved in a wide range of biological processes such as blood coagulation, membrane fusion and cell apoptosis in cooperation with calcium-binding proteins. Although it is commonly acknowledged that calcium ions interact with PS to form complexes that induce the phase separation in mixed bilayers, the PS domain formation has not yet been observed in molecular dynamics (MD) simulations. The effect of monovalent (MI) and divalent (MII) cationic radii is explored on lipid domain formation in mixed zwitterionic-anionic lipid bilayers. We propose a mechanism of the formation of divalent-cation induced lipid domains based on the results of a series of MD simulations with our Water-Explicit Polarizable MEMbrane (WEPMEM) coarse-grained model, which uses phosphatidylcholine (PC) as a model for zwitterionic and phosphatidylserine for anionic lipids. The network of gel-like PS aggregates is only observed with both monovalent and divalent metal ions of appropriate radii. More ordering and closer packing of PS lipids are observed within the domains, which correlates with bilayer thickness, curvature and asymmetry in lipid compositions of both leaflets. The results of the simulations reveal that the PS domain consists of MII-mediated PS dimer/trimer complexes bridged by monovalent ions MI and provide a stereochemical insight in understanding calcium-induced phase separation.