The transbilayer distribution of polyunsaturated phospholipids determines their facilitating effect on membrane deformation.

In the cell, membrane deformation and fission (collectively referred to as 'budding') is driven by specific protein machineries but is also influenced by lipid composition. We previously reported that phospholipids with polyunsaturated acyl chains facilitate membrane budding because they adapt their shape to membrane curvature, thereby decreasing membrane bending rigidity. The facilitating effect of polyunsaturated lipids was observed in experiments and simulations performed on membranes where the two bilayer leaflets had the same lipid composition. However, biological membranes are generally asymmetric. Here, we present coarse-grained molecular dynamics simulations on asymmetric phospholipid bilayers undergoing deformation via a pulling force along the bilayer normal. One leaflet contains monounsaturated C18:0-C18:1-phospholipids, whereas the opposite leaflet contains polyunsaturated C18:0-C22:6-phospholipids. When present in the monolayer orientated towards the pulling force and thereby in the convex face of the forming tube, C18:0-C22:6-phospholipids facilitate membrane tubulation. In contrast, C18:0-C22:6-phospholipids in the concave face of the tube have no effect. Analysis of lipid shape indicates that these contrasting effects arise from the superior ability of polyunsaturated phospholipids to swell in the convex leaflet, whereas mono and polyunsaturated phospholipids behave similarly in the concave leaflet. The leaflet-dependent effect of polyunsaturated phospholipids matches well their asymmetric distribution in biological membranes, notably in synaptic vesicles, which are produced by the fastest budding event in the body.

PackMem: A Versatile Tool to Compute and Visualize Interfacial Packing Defects in Lipid Bilayers.

The analysis of the structural organization of lipid bilayers is generally performed across the direction normal to the bilayer/water interface, whereas the surface properties of the bilayer at the interface with water are often neglected. Here, we present PackMem, a bioinformatic tool that performs a topographic analysis of the bilayer surface from various molecular dynamics simulations. PackMem unifies and rationalizes previous analyses based on a Cartesian grid. The grid allows identification of surface regions defined as lipid-packing defects where lipids are loosely packed, leading to cavities in which aliphatic carbons are exposed to the solvent, either deep inside or close to the membrane surface. Examples are provided to show that the abundance of lipid-packing defects varies according to the temperature and to the bilayer composition. Because lipid-packing defects control the adsorption of peripheral proteins with hydrophobic insertions, PackMem is instrumental for us to understand and quantify the adhesive properties of biological membranes as well as their response to mechanical perturbations such as membrane deformation.

Alternative dimerization interfaces in the glucocorticoid receptor-α ligand binding domain.

BACKGROUND: Nuclear hormone receptors (NRs) constitute a large family of multi-domain ligand-activated transcription factors. Dimerization is essential for their regulation, and both DNA binding domain (DBD) and ligand binding domain (LBD) are implicated in dimerization. Intriguingly, the glucocorticoid receptor-α (GRα) presents a DBD dimeric architecture similar to that of the homologous estrogen receptor-α (ERα), but an atypical dimeric architecture for the LBD. The physiological relevance of the proposed GRα LBD dimer is a subject of debate. METHODS: We analyzed all GRα LBD homodimers observed in crystals using an energetic analysis based on the PISA and on the MM/PBSA methods and a sequence conservation analysis, using the ERα LBD dimer as a reference point. RESULTS: Several dimeric assemblies were observed for GRα LBD. The assembly generally taken to be physiologically relevant showed weak binding free energy and no significant residue conservation at the contact interface, while an alternative homodimer mediated by both helix 9 and C-terminal residues showed significant binding free energy and residue conservation. However, none of the GRα LBD assemblies found in crystals are as stable or conserved as the canonical ERα LBD dimer. GRα C-terminal sequence (F-domain) forms a steric obstacle to the canonical dimer assembly in all available structures. CONCLUSIONS: Our analysis calls for a re-examination of the currently accepted GRα homodimer structure and experimental investigations of the alternative architectures. GENERAL SIGNIFICANCE: This work questions the validity of the currently accepted architecture. This has implications for interpreting physiological data and for therapeutic design pertaining to glucocorticoid research.

Acyl chain asymmetry and polyunsaturation of brain phospholipids facilitate membrane vesiculation without leakage.

Phospholipid membranes form cellular barriers but need to be flexible enough to divide by fission. Phospholipids generally contain a saturated fatty acid (FA) at position sn1 whereas the sn2-FA is saturated, monounsaturated or polyunsaturated. Our understanding of the impact of phospholipid unsaturation on membrane flexibility and fission is fragmentary. Here, we provide a comprehensive view of the effects of the FA profile of phospholipids on membrane vesiculation by dynamin and endophilin. Coupled to simulations, this analysis indicates that: (i) phospholipids with two polyunsaturated FAs make membranes prone to vesiculation but highly permeable; (ii) asymmetric sn1-saturated-sn2-polyunsaturated phospholipids provide a tradeoff between efficient membrane vesiculation and low membrane permeability; (iii) When incorporated into phospholipids, docosahexaenoic acid (DHA; omega-3) makes membranes more deformable than arachidonic acid (omega-6). These results suggest an explanation for the abundance of sn1-saturated-sn2-DHA phospholipids in synaptic membranes and for the importance of the omega-6/omega-3 ratio on neuronal functions.