Interaction of Conical Membrane Inclusions: Effect of Lateral Tension

Considering two rigid conical inclusions embedded in a membrane subject to lateral tension, we study the membrane-mediated interaction between these inclusions that originates from the hat-shaped membrane deformations associated with the cones. At non-vanishing lateral tensions, the interaction is found to depend on the orientation of the cones with respect to the membrane plane. The interaction of inclusions of equal orientation is repulsive at all distances between them, while the inclusions of opposite orientation repel each other at small separations, but attract each other at larger ones. Both the repulsive and attractive forces become stronger with increasing lateral tension. This is different from what has been predicted on the basis of the same static model for the case of vanishing lateral tension. Without tension, the inclusions repel each other at all distances independently of their relative orientation. We conclude that lateral tension may induce the aggregation of conical membrane inclusions.Comment: 10 pages (revtech), 5 figures (postscript

Accessory mutations balance the marginal stability of the HIV-1 protease in drug resistance

The HIV-1 protease is a major target of inhibitor drugs in AIDS therapies. The therapies are impaired by mutations of the HIV-1 protease that can lead to resistance to protease inhibitors. These mutations are classified into major mutations, which usually occur first and clearly reduce the susceptibility to protease inhibitors, and minor, accessory mutations that occur later and individually do not substantially affect the susceptibility to inhibitors. Major mutations are predominantly located in the active site of the HIV-1 protease and can directly interfere with inhibitor binding. Minor mutations, in contrast, are typically located distal to the active site. A central question is how these distal mutations contribute to resistance development. In this article, we present a systematic computational investigation of stability changes caused by major and minor mutations of the HIV-1 protease. As most small single-domain proteins, the HIV-1 protease is only marginally stable. Mutations that destabilize the folded, active state of the protease therefore can shift the conformational equilibrium towards the unfolded, inactive state. We find that the most frequent major mutations destabilize the HIV-1 protease, whereas roughly half of the frequent minor mutations are stabilizing. An analysis of protease sequences from patients in treatment indicates that the stabilizing minor mutations are frequently correlated with destabilizing major mutations, and that highly resistant HIV-1 proteases exhibit significant fractions of stabilizing mutations. Our results thus indicate a central role of minor mutations in balancing the marginal stability of the protease against the destabilization induced by the most frequent major mutation

Segregation of receptor-ligand complexes in cell adhesion zones: Phase diagrams and role of thermal membrane roughness

The adhesion zone of immune cells, the 'immunological synapse', exhibits characteristic domains of receptor-ligand complexes. The domain formation is likely caused by a length difference of the receptor-ligand complexes, and has been investigated in experiments in which T cells adhere to supported membranes with anchored ligands. For supported membranes with two types of anchored ligands, MHCp and ICAM1, that bind to the receptors TCR and LFA1 in the cell membrane, the coexistence of domains of TCR-MHCp and LFA1-ICAM1 complexes in the cell adhesion zone has been observed for a wide range of ligand concentrations and affinities. For supported membranes with long and short ligands that bind to the same cell receptor CD2, in contrast, domain coexistence has been observed for a rather narrow ratio of ligand concentrations. In this article, we determine detailed phase diagrams for cells adhering to supported membranes with a statistical-physical model of cell adhesion. We find a characteristic difference between the adhesion scenarios in which two types of ligands in a supported membrane bind (i) to the same cell receptor or (ii) to two different cell receptors, which helps to explain the experimental observations. Our phase diagrams fully include thermal shape fluctuations of the cell membranes on nanometer scales, which lead to a critical point for the domain formation and to a cooperative binding of the receptors and ligands.Comment: 23 pages, 6 figure

Lateral diffusion of receptor-ligand bonds in membrane adhesion zones: Effect of thermal membrane roughness

The adhesion of cells is mediated by membrane receptors that bind to complementary ligands in apposing cell membranes. It is generally assumed that the lateral diffusion of mobile receptor-ligand bonds in membrane-membrane adhesion zones is slower than the diffusion of unbound receptors and ligands. We find that this slowing down is not only caused by the larger size of the bound receptor-ligand complexes, but also by thermal fluctuations of the membrane shape. We model two adhering membranes as elastic sheets pinned together by receptor-ligand bonds and study the diffusion of the bonds using Monte Carlo simulations. In our model, the fluctuations reduce the bond diffusion constant in planar membranes by a factor close to 2 in the biologically relevant regime of small bond concentrations.Comment: 6 pages, 5 figures; to appear in Europhysics Letter

Cooperative stabilization of close-contact zones leads to sensitivity and selectivity in T-cell recognition

T cells are sensitive to 1 to 10 foreign-peptide-MHC complexes among a vast majority of self-peptide-MHC complexes, and discriminate selectively between peptide-MHC complexes that differ not much in their binding affinity to T-cell receptors (TCRs). Quantitative models that aim to explain this sensitivity and selectivity largely focus on single TCR/peptide-MHC complexes, but T cell adhesion involves a multitude of different complexes. In this article, we demonstrate in a three-dimensional computational model of T-cell adhesion that the cooperative stabilization of close-contact zones is sensitive to one to three foreign-peptide-MHC complexes and occurs at a rather sharp threshold affinity of these complexes, which implies selectivity. In these close-contact zones with lateral extensions of hundred to several hundred nanometers, few TCR/foreign-peptide-MHC complexes and many TCR/self-peptide-MHC complexes are segregated from LFA-1/ICAM-1 complexes that form at larger membrane separations. Previous high-resolution microscopy experiments indicate that the sensitivity and selectivity in the formation of closed-contact zones reported here are relevant for T-cell recognition, because the stabilization of close-contact zones by foreign, agonist peptide-MHC complexes precedes T-cell signaling and activation in the experiments

Indirect interactions of membrane-adsorbed cylinders

Biological and biomimetic membranes often contain aggregates of embedded or adsorbed macromolecules. In this article, the indirect interactions of cylindrical objects adhering to a planar membrane are considered theoretically. The adhesion of the cylinders causes a local perturbation of the equilibrium membrane shape, which leads to membrane-mediated interactions. For a planar membrane under lateral tension, the interaction is repulsive for a pair of cylinders adhering to the same side of the membrane, and attractive for cylinders adhering at opposite membrane sides. For a membrane in an external harmonic potential, the interaction of adsorbed cylinders is always attractive and increases if forces perpendicular to the membrane act on the cylinders.Comment: 9 pages, 8 figures; typos correcte

Lateral phase separation of confined membranes

We consider membranes interacting via short, intermediate and long stickers. The effects of the intermediate stickers on the lateral phase separation of the membranes are studied via mean-field approximation. The critical potential depth of the stickers increases in the presence of the intermediate sticker. The lateral phase separation of the membrane thus suppressed by the intermediate stickers. Considering membranes interacting with short and long stickers, the effect of confinement on the phase behavior of the membranes is also investigated analytically