Domain Formation Induced by the Adsorption of Charged Proteins on Mixed Lipid Membranes

Abstract

Peripheral proteins can trigger the formation of domains in mixed fluid-like lipid membranes. We analyze the mechanism underlying this process for proteins that bind electrostatically onto a flat two-component membrane, composed of charged and neutral lipid species. Of particular interest are membranes in which the hydrocarbon lipid tails tend to segregate owing to nonideal chain mixing, but the (protein-free) lipid membrane is nevertheless stable due to the electrostatic repulsion between the charged lipid headgroups. The adsorption of charged, say basic, proteins onto a membrane containing anionic lipids induces local lipid demixing, whereby charged lipids migrate toward (or away from) the adsorption site, so as to minimize the electrostatic binding free energy. Apart from reducing lipid headgroup repulsion, this process creates a gradient in lipid composition around the adsorption zone, and hence a line energy whose magnitude depends on the protein's size and charge and the extent of lipid chain nonideality. Above a certain critical lipid nonideality, the line energy is large enough to induce domain formation, i.e., protein aggregation and, concomitantly, macroscopic lipid phase separation. We quantitatively analyze the thermodynamic stability of the dressed membrane based on nonlinear Poisson-Boltzmann theory, accounting for both the microscopic characteristics of the proteins and lipid composition modulations at and around the adsorption zone. Spinodal surfaces and critical points of the dressed membranes are calculated for several different model proteins of spherical and disk-like shapes. Among the models studied we find the most substantial protein-induced membrane destabilization for disk-like proteins whose charges are concentrated in the membrane-facing surface. If additional charges reside on the side faces of the proteins, direct protein-protein repulsion diminishes considerably the propensity for domain formation. Generally, a highly charged flat face of a macroion appears most efficient in inducing large compositional gradients, hence a large and unfavorable line energy and consequently lateral macroion aggregation and, concomitantly, macroscopic lipid phase separation.

Regulation of anionic lipids in binary membrane upon the adsorption of polyelectrolyte: A Monte Carlo simulation

“…39 Khelashvili et al employed a dynamic Monte Carlo simulation to explore the protein diffusion on mixed membrane and corresponding charged lipid reorganization. 10 Various coarse-grained models, which consider the lipids within regular solution theory and the macromolecule as a homogeneous flat surface, 40 a finite cylinder, 41,42 hard spheres, 43 rectangles, 44 or as a flexible polyelectrolyte, 8,45 have been developed. These models provided straightforward descriptions to the macromolecule/PIP 2 interaction, and showed that the extent of lipid segregation, the lipid dynamic heterogeneity behaviors, and the corresponding entropy and free energy variations are critically dependant on the shape, charge, and concentration of the adsorbing macromolecules.…”

“…10,20,21,35 Studies supported the conclusion that the variation of the net charge of macromolecules and salt solution ionic concentration may drastically affect the segregation of charged lipids 5,37 and mediate macromolecules adsorption on the membrane. 42 Thus, systematic investigations of the influence of the cooperativity effect and electrostatic interaction of the macromolecules, and solution screening effect on the static and kinetic properties of PIP 2 , as well as the relative macromolecule dynamics can help not only the understanding of the biophysical processes, but also the development of disease therapy by controlling the segregation and mobility of PIP 2 . 1 In the previous study, we employed Monte Carlo simulation to investigate the influence of solution ionic strength on adsorption/desorption behaviors and the corresponding conformational variations of the polyelectrolyte on mixed lipid membranes.…”

Tracking peptide–membrane interactions: Insights from in situ coupled confocal-atomic force microscopy imaging of NAP-22 peptide insertion and assembly

“…The mechanism by which charged peripheral membrane proteins can induce domain formation has recently been proposed (Mbamala et al, 2005). Recently, it was demonstrated that NAP-22 peptide inserts into membranes, sequesters PtdIns(4,5)P 2 in a cholesteroldependent manner, and induces formation of a cholesterol-depleted domain (Epand et al, 2004(Epand et al, , 2005a.…”

Polyelectrolyte condensation in bulk, at surfaces, and under confinement

“…Accordingly, the number of theoretical and computational studies on the interaction of proteins [72][73][74][75][76] and polyelectrolytes [77][78][79] with fluid lipid membranes has increased in recent years. It was observed that the adsorption of macromolecules induces the demixing of the lipids in the membrane and that the demixing, in turn, increases the binding energy of the macromolecule to the membrane.…”