membrane asymmetry

Figure 1. Computational investigation of membrane asymmetry and interleaflet communication. Atomistic and coarse-grained models provide experimentally-inaccessible level of detail into the effects of asymmetry on membrane properties.

membrane asymmetry in silico

Membrane asymmetry can change bilayer properties in unpredictable ways. While a wet lab experiment can provide macroscopic observables of the asymmetry effects, molecular dynamics (MD) simulations offer a glimpse into the detailed mechanisms underlying these effects (Fig. 1). Through MD studies it became clear that asymmetric bilayers cannot be defined by their leaflet lipid compositions alone, but instead their properties depend on the amount of differential stress (or leaflet tension) induced by the relative lipid abundances in the two leaflets. At present, differential stress can be quantified only with MD simulations and we are developing various ways of coupling results from simulation trajectories with experiments in order to experimentally access and characterize these asymmetry-induced mechanical stresses in the membrane leaflets.

Figure 2. Protocol for the preparation of synthetic asymmetric liposomes. Extruded asymmetric liposomes with well defined leaflet lipid compositions offer an invaluable tool in the experimental investigation of membrane asymmetry.

membrane asymmetry in vitro

Membrane asymmetry represents a non-equilibrium state that cells maintain with the help of specialized lipid-translocating enzymes. That is why creating protein-free asymmetric model membranes in vitro has been a challenging task. With a group of collaborators, we have developed protocols for the preparation and compositional characterization of asymmetric extruded liposomes frequently applied in a wide array of biophysical studies (Fig. 2). These tools have been used to examine various bilayer properties including protein-membrane interactions, and represent well-defined experimental systems that can be coupled with simulations to test mechanistic hypotheses and push the study of membrane asymmetry even further.

Figure 3. Updated model of lipid and cholesterol organization in mammalian plasma membranes. The plasma membrane bilayer is asymmetric both in composition and total abundance of phospholipids and cholesterol, with fewer phospholipids and more cholesterol in the exoplasmic leaflet. This organization affects the membrane's biophysical properties (permeability, mechanical stresses, interactions with proteins) and physiological roles (cellular cholesterol homeostasis).

membrane asymmetry in mammalian cells

The cell plasma membrane (PM) is the primary barrier separating the cell interior from the extracellular environment. The PM actively participates in myriad biological processes. This functional diversity is facilitated by tight control over the composition of its lipid bilayer, which allows for dynamic regulation of membrane permeability, flexibility and modes of interaction between proteins. One example of this regulation is the asymmetric distribution of various structurally diverse lipids across the two leaflets of the PM bilayer, which is a conserved and functionally critical feature of essentially all eukaryotic cells. While the compositional asymmetry of cell PMs has been known since the 1970s, we and collaborators recently uncovered evidence for the existence of a complementary number asymmetry of the membrane components. Through a combination of various experimental and computational techniques, we found that mammalian plasma membranes have fewer phospholipids and more cholesterol in their exoplasmic leaflets, and more phospholipids and less cholesterol in their cytoplasmic leaflets (Fig. 3). This previously-unconceivable arrangement of the lipid bilayer has unique biophysical consequences for the plasma membrane and its roles in cell physiology, and represents a completely new dimension of membrane organization that we are just now starting to explore.

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