Assessing the Nature of Lipid Raft Membranes

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Abstract
The paradigm of biological membranes has recently gone through a major update. Instead of being fluid and homogeneous, recent studies suggest that membranes are characterized by transient domains with varying fluidity. In particular, a number of experimental studies have revealed the existence of highly ordered lateral domains rich in sphingomyelin and cholesterol (CHOL). These domains, called functional lipid rafts, have been suggested to take part in a variety of dynamic cellular processes such as membrane trafficking, signal transduction, and regulation of the activity of membrane proteins. However, despite the proposed importance of these domains, their properties, and even the precise nature of the lipid phases, have remained open issues mainly because the associated short time and length scales have posed a major challenge to experiments. In this work, we employ extensive atom-scale simulations to elucidate the properties of ternary raft mixtures with CHOL, palmitoylsphingomyelin (PSM), and palmitoyloleoylphosphatidylcholine. We simulate two bilayers of 1,024 lipids for 100 ns in the liquid-ordered phase and one system of the same size in the liquid-disordered phase. The studies provide evidence that the presence of PSM and CHOL in raft-like membranes leads to strongly packed and rigid bilayers. We also find that the simulated raft bilayers are characterized by nanoscale lateral heterogeneity, though the slow lateral diffusion renders the interpretation of the observed lateral heterogeneity more difficult. The findings reveal aspects of the role of favored (specific) lipid–lipid interactions within rafts and clarify the prominent role of CHOL in altering the properties of the membrane locally in its neighborhood. Also, we show that the presence of PSM and CHOL in rafts leads to intriguing lateral pressure profiles that are distinctly different from corresponding profiles in nonraft-like membranes. The results propose that the functioning of certain classes of membrane proteins is regulated by changes in the lateral pressure profile, which can be altered by a change in lipid content. Biological membranes are complex 2-D assemblies of various lipid species and membrane proteins. For long, it was thought that the main role of lipid membranes is to provide a homogeneous, liquid-like platform for membrane proteins to carry out their functions as they diffuse freely in the membrane plane. Recently, that view has changed. It has become evident that several lipid environments with different physical properties may coexist, and that the properties of the different lipid domains may play an active role in regulating the conformational state and dynamic sorting of membrane proteins. We have carried out atom-scale computer simulations for three-component lipid bilayers, so-called lipid rafts, rich in cholesterol and sphingolipids. They show that arising from the local interactions between the lipid species, the elastic and dynamic properties of the membranes depend strongly on the lipid composition. The changes in elastic properties are suggested to alter the functional states of various membrane proteins. Changes in lipid composition are also shown to alter the distribution of local pressure inside the membrane. This is likely to affect proteins that undergo large anisotropic conformational changes between the functional states, such as the ion channel MscL, used as an example here. A great number of important physiological phenomena, such as transmitting neural impulses or trafficking molecules in and out of the cell, involve activation of membrane proteins, so it is relevant to understand all factors affecting them. Our findings support the idea that general physical properties of the lipid environment are capable of regulating membrane proteins.