Mbamala, E. C. ; Ben-Shaul, A. ; May, S. .
Domain Formation Induced By The Adsorption Of Charged Proteins On Mixed Lipid Membranes.
BIOPHYSICAL JOURNAL 2005,
88, 1702-1714.
תקצירPeripheral proteins can trigger the formation of domains in mixed. uid- like lipid membranes. We analyze the mechanism underlying this process for proteins that bind electrostatically onto a. at two- component membrane, composed of charged and neutral lipid species. Of particular interest are membranes in whichthe 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 islarge 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 disklike shapes. Among the models studied we. nd 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 fordomain formation. Generally, a highly charged. at face of a macroion appears most ef. cient in inducing large compositional gradients, hence a large and unfavorable line energy and consequently lateral macroion aggregation and, concomitantly, macroscopic lipid phase separation.
Tzlil, S. ; Ben-Shaul, A. .
Flexible Charged Macromolecules On Mixed Fluid Lipid Membranes: Theory And Monte Carlo Simulations.
BIOPHYSICAL JOURNAL 2005,
89, 2972-2987.
תקצירFluid membranes containing charged lipids enhance binding of oppositely charged proteins by mobilizing these lipids into the interaction zone, overcoming the concomitant entropic losses due to lipid segregation and lower conformational freedom upon macromolecule adsorption. We study this energetic-entropic interplay using Monte Carlo simulations and theory. Our model system consists of a flexible cationic polyelectrolyte, interacting, via Debye-Huckel and short-ranged repulsive potentials, with membranes containing neutral lipids, 1% tetravalent, and 10% ( or 1%) monovalent anionic lipids. Adsorption onto a fluid membrane is invariably stronger than to an equally charged frozen or uniform membrane. Although monovalent lipids may suffice for binding rigid macromolecules, polyvalent counter-lipids ( e. g., phosphatidylinositol 4,5 bisphosphate), whose entropy loss upon localization is negligible, are crucial for binding flexible macromolecules, which lose conformational entropy upon adsorption. Extending Rosenbluth’s Monte Carlo scheme we directly simulate polymer adsorption on fluid membranes. Yet, we argue that similar information could be derived from a biased superposition of quenched membrane simulations. Using a simple cell model we account for surface concentration effects, and show that the average adsorption probabilities on annealed and quenched membranes coincide at vanishing surface concentrations. We discuss the relevance of our model to the electrostatic-switch mechanism of, e. g., the myristoylated alanine-rich C kinase substrate protein.
Zemel, A. ; Ben-Shaul, A. ; May, S. .
Perturbation Of A Lipid Membrane By Amphipathic Peptides And Its Role In Pore Formation.
EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS 2005,
34, 230-242.
תקצירWe study the structural and energetic consequences of (α-helical) amphipathic peptide adsorption onto a lipid membrane and the subsequent formation of a transmembrane peptide pore. Initially, each peptide binds to the membrane surface, with the hydrophobic face of its cylinder-like body inserted into the hydrocarbon core. Pore formation results from subsequent peptide crowding, oligomerization, and eventually reorientation along the membrane normal. We have theoretically analyzed three peptide-membrane association states: interfacially-adsorbed monomeric and dimeric peptides, and the multi-peptide transmembrane pore state. Our molecular-level model for the lipid bilayer is based on a combination of detailed chain packing theory and a phenomenological description of the headgroup region. We show that the membrane perturbation free energy depends critically on peptide orientation: in the transmembrane pore state the lipid perturbation energy, per peptide, is smaller than in the adsorbed state. This suggests that the gain in conformational freedom of the lipid chains is a central driving force for pore formation. We also find a weak, lipid-mediated, gain in membrane perturbation free energy upon dimerization of interfacially-adsorbed peptides. Although the results pertain mainly to weakly-charged peptides, they reveal general properties of the interaction of amphipathic peptides with lipid membranes.
Chen, C. P. ; Posy, S. ; Ben-Shaul, A. ; Shapiro, L. ; Honig, B. H. .
Specificity Of Cell-Cell Adhesion By Classical Cadherins: Critical Role For Low-Affinity Dimerization Through Beta-Strand Swapping.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2005,
102, 8531-8536.
תקצירCadherins constitute a family of cell-surface proteins that mediate intercellular adhesion through the association of protomers presented from juxtaposed cells. Differential cadherin expression leads to highly specific intercellular interactions in vivo. This cell-cell specificity is difficult to understand at the molecular level because individual cadherins within a given subfamily are highly similar to each other both in sequence and structure, and they dimerize with remarkably low binding affinities. Here, we provide a molecular model that accounts for these apparently contradictory observations. The model is based in part on the fact that cadherins bind to one another by ‘‘swapping’’ the N-terminal beta-strands of their adhesive domains. An inherent feature of strand swapping (or, more generally, the domain swapping phenomenon) is that ‘‘closed’’ monomeric conformations act as competitive inhibitors of dinner formation, thus lowering affinities even when the dimer interface has the characteristics of high-affinity complexes. The model describes quantitatively how small affinity differences between low-affinity cadherin dimers are amplified by multiple cadherin interactions to establish large specificity effects at the cellular level. It is shown that cellular specificity would not be observed if cadherins bound with high affinities, thus emphasizing the crucial role of strand swapping in cell-cell adhesion. Numerical estimates demonstrate that the strength of cellular adhesion is extremely sensitive to the concentration of cadherins expressed at the cell surface. We suggest that the domain swapping mechanism is used by a variety of cell-adhesion proteins and that related mechanisms to control affinity and specificity are exploited in other systems.