key: cord-0766545-qdbgkm53
authors: Kinnun, Jacob J.; Bolmatov, Dima; Lavrentovich, Maxim O.; Katsaras, John
title: Lateral Heterogeneity and Domain Formation in Cellular Membranes
date: 2020-09-15
journal: Chem Phys Lipids
DOI: 10.1016/j.chemphyslip.2020.104976
sha: 183022fe63d8c0d426a0f01db4a57d7004c4d413
doc_id: 766545
cord_uid: qdbgkm53

As early as the development of the fluid mosaic model for cellular membranes, researchers began observing the telltale signs of lateral heterogeneity. Over the decades this has led to the development of the lipid raft hypothesis and the ensuing controversy that has unfolded. Here, we review the physical concepts behind domain formation in lipid membranes, both of their structural and dynamic origins. This, then leads into a discussion of coarse-grained, phenomenological approaches that describe the wide range of phases associated with lipid lateral heterogeneity. We use these physical concepts to describe the interaction between raft-lipid species, such as long-chain saturated lipids, sphingomyelin, and cholesterol with non-raft forming lipids, such as those with short acyl chains or unsaturated fatty acids. While debate has persisted on the biological relevance of lipid domains, recent research, described here, continues to identify biological roles for rafts and new experimental approaches have revealed the existence of lipid domains in living systems. Given the recent progress on both the biological and structural aspects of raft formation, the research area of membrane lateral heterogeneity will not only expand, but will continue to produce exciting results.

The fluid mosaic model of membranes was proposed by Singer and Nicolson in 1972, 1 and almost immediately, there were reports showing the existence of membrane lateral heterogeneity 2 . 3 By the late 1970's, it was suggested that lipids could segregate into liquid disordered and liquid ordered domains. 4 Over the next decade, research showed that proteins could also co-localize 5 6 7 , 8 and in some cases, preferentially associate with lipids, such as sphingomyelin. 9 In the early 1990's, experiments focusing on cholesterol in model membranes showed the sterol's ability to increase lateral heterogeneity 10 11 and other studies, such as those using detergents to extract biomolecules from natural membranes, soon followed demonstrating protein co-localization with sphingomyelin and cholesterol 12 13 14 15 . 16 Eventually, these data led to the hypothesis that sphingomyelin and cholesterol formed liquid ordered domains, called "rafts", in which proteins could associated with 17 . 18 Although it was shown that some proteins had a preference for certain lipids, the idea that these would form large domains of functional significance remained controversial. However, recent research has revealed evidence for domain formation, consistent with lipid rafts, in fully functional, living cells 19 . 20 In this review, we discuss the concepts behind lipid domain formation in membranes, the biomolecules that they are made of, and their biological significance.

2 J o u r n a l P r e -p r o o f

The propensity for domain formation results from the interaction energy between chemically distinct lipids and proteins. For example, unfavorable interaction energies can result from lipids with different length fatty acid chains, forming for example, different bilayer thicknesses residing near each other. Some of these unfavorable interactions can be eliminated or minimized by sequestering lipids of similar length within a domain. To model this, an interaction energy, i.e., the so-called called line tension, λ, is used, and which is defined as:

where E b is the total interaction energy at the domain boundary and L b is the length of the domain boundary. 21 Note, that the total interaction energy is proportional to the domain boundary length, but the line tension, is not.

In general, the greater the line tension, the greater the propensity for domain formation.

Line tension can be thought of as a string surrounding the domain perimeter that tightens as a function of an increasing unfavorable interaction energy between the the domain and its surroundings. Note, that line tension should be considered in relation to the repulsive electrostatic forces that exist between the different lipids. points in phase separation studies. 23, 24 Further, experiments have revealed that domain formation is to some extent, dependent on the collective membrane material properties and long-range fluctuations, 25 which will be discussed later. Thus, line tension, itself, can vary as a function of system size, under certain circumstances.

In addition to domain size having an effect on line tension, it is known that lipid-lipid repulsive interactions -which limit domain formation -also affect line tension. One way to account for lipid-lipid repulsive forces that counteract line tension, is to treat each lipid phase as a density of dipoles. What is important here, is not the absolute dipolar density, but the dipole density difference, ∆m, where lipids of one phase redistribute into the other phase in order to reduce repulsive dipolar interactions. The energy per molecule, E/N , for a circular domain can be written in terms of the opposing line tension and dipolar density difference as:

where a 0 is the area per molecule, R is the domain radius, ε is the dielectric constant of the interfacial water, ε 0 is the permittivity of free space, e is Euler's number, and δ is the molecular cut-off distance ∼ 0.5nm 26 Lipids and membrane proteins have varying intrinsic hydrophobic thicknesses. Coexistence of these species within a membrane results in local deformations at boundaries, where lipids splay and tilt to accommodate different thicknesses (see fig. 1 ). However, these deformations have an associated energy cost that results in line tension. Energetics of local deformation can be discussed in terms of material properties, such as the splay elastic modulus (B), tilt modulus (K), and the intrinsic curvature (J) between two domains. If we consider two domains with thickness difference, δ, and an average thickness, h 0 , the line tension at the domain boundary can be written as: 

A feature of increasing importance is the packing defects between membrane lipids. These are introduced when the structure of a lipid is unable to conform to its neighbor. Defects can be therefore be introduced as a result of the presence of unsaturated acyl chains or methylated segments that do not pack well with rigid moieties, such as the hydrocarbon rings in sterols, as shown in Fig. 2c . Akin to material rigidities -as discussed in the previous section -increasing biomolecule rigidity enhances packing mismatch, which increases line tension. In terms of specific theoretical energetics, this contribution to line tension is less 6 J o u r n a l P r e -p r o o f Figure 2 : (a) The registration of domains across membrane leaflets maximizes dynamics, is entropically favorable, and is one mechanism for domain coalescence (adapted from Haataja et al. 36 

where a is the characteristic length of the monolayer that lies between the lipid headgroup diameter and monolayer thickness. 25 An increasing bending rigid difference between ordered and disordered lipid phases increases the value of the logarithm in Eq. 4. This repulsive energy increase can result in co-alignment of rigid domains across bilayer leaflets or domains aggregating to more rigid areas of the membrane, such as those with proteins. For the case of domain registration across bilayer leaflets, it has been determined experimentally that domains with similar bending rigidiities can coalesce. 44 It has also been observed that domains are able to coalesce across adjacent bilayers, 45 and membrane undulations are thought to play a similar role 46 36 . 25 Moreover, effects of acyl chain packing across bilayer leaflets should not be discounted, as there is evidence that leaflets can influence each other's molecular order. 47 Thus the packing between leaflets may influence domain registration and ultimately, domain formation. 

Evidence for lipid-driven lateral heterogeneity in membranes began to appear in lipid mixtures, such as dimyristoylphosphatidylcholine (14 carbon acyl chains) mixed with distearoylphosphatidylcholine (18 carbon acyl chains) 50 51 52 . 53 In general, longer-chained, unsaturated lipids tend to be more ordered, 54 The entropic difference between these two states results in a tension at domain boundaries 37 93 (see fig. 2b ) and adds another possible mechanism for cholesterol increasing domain size through registration.

Although specific bonding between cholesterol and sphingomyelin may play a major role in cholesterol's ability to increase the size of domains, the effect of non-raft domains should not be discounted. There is research showing that increasing the unsaturated lipid presence of non-raft lipid constituents drives increasing domain size, implying that acyl packing effects may be a big contributor to domain size. It has also been suggested that the "push" mechanism that drives cholesterol from non-raft domains is equally important as the "pull" mechanism, where cholesterol is incorporated into rafts 94 

Many proteins are relatively rigid and require a hydrophobic surface of sufficient thickness for them to incorporate "properly" into the membrane. Differences between the protein's hydrophobic portions and those of the surrounding lipid membrane can result in hydrophobic mismatch, i.e., increased line tension (see fig. 1c Early on, some research indicated that certain proteins preferential interact with sphin-gomyelin 14 . 97 Since proteins can increase membrane thickness, it is likely that the ordering nature of sphingomyelin reduces membrane tension by deforming the membrane around proteins. Also, it has previously been discussed that the nature of sphingomyelin's acyl chains allows for them to be compatible with the rigid cholesterol. Since proteins can also be rigid, it is then possible that sphingoymelin is able to interact with proteins in a manner similar to that with cholesterol. It should also be pointed out that proteins, themselves, can form domains on the membrane surface, e.g., scaffolding proteins 97 . 98 Often their organization is guided by electrostatics through specific charged amino acids, leading to oligomerization. 99 Although some do not penetrate into the bilayer, they do introduce a region of increased local rigidity, which may be sufficient to cause ordered domain registration of apposing bilayer leaflets 25 . 

where the units are defined such that the coefficients of the quartic terms are unitless. This simple model has three parameters: i.e., κ, r, and µ, with the latter two parameters derived from the thermodynamic potential V [φ] and where κ is the rescaled surface tension.

Often, the fourth-order derivative term is ignored. This is acceptable as long as κ > 0 in Eq. (5). As a result, the fourth-order derivative term becomes irrelevant with respect to the renormalization group and the dominant term becomes the second-order derivative. r is a tunable parameter across the mixing/demixing phase transition, which, in the mean-field, would occur at r = µ 2 /4 or where phase separation takes place. Conversely, for r > µ 2 /4, the potential V [φ] is minimized around φ = 0 and we would expect no phase separation, but rather a fluctuating, disordered mixture of the liquid-ordered and liquid-disordered regions with a characteristic correlation length ξ ∼ κ/r.

We may also be a somewhat more specific and identify the constant values φ o,d for which the potential is at a minimum in the phase separated regime with r < µ 2 /4. For 0 < r < µ 2 /4, the potential V [φ] has two minima at constant values φ = φ d = 0 and

respectively. Note that when µ = 0, this transition would have a first-order character and the potential will have a local maximum between the two minima (i.e., a thermodynamic barrier to transitioning between the liquid-disordered and liquid-ordered phases). If µ = 0, the two minima in the free energy become degenerate at φ = 0 at the transition (r = 0) so that there is no thermodynamic barrier and the transition is second-order (continuous). Thermal fluctuations change this picture, somewhat, as the distinction between an unstable and a metastable phase becomes ambiguous when thermal fluctuations are taken into account. 100 In lipid vesicles, it is easy to tune across the mixing/demixing transition by varying the temperature. In biological cells, however, the situation is more complicated as it is unclear whether or not the cell membrane is at equilibrium, whereby these phases may not be meaningful. Nevertheless, the free energy in Eq. (5) is useful as a conceptual tool.

We may use it as a basis for constructing the dynamics of the lipid phases by employing an appropriate dynamical model. 101 For instance, it has been recently argued that natural cells tune their membranes such that, they have compositions near criticality (µ = 0 and r ≈ 0). 102, 103 Through dynamical processes, such as lipid diffusion, the free energy in Eq. (5) trends towards minimization. As the lipid membrane is fluid, the most appropriate model would include the hydrodynamic coupling of the lipids across the membrane. 104 Another crucial aspect of the dynamics is the conservation of total lipids, which means that the integrated order parameter, dx φ(x), is a constant (typically zero for equal proportions of liquid-ordered and liquid-disordered regions). Excluding the hydrodynamics and thermal fluctuations, the time-dependence of the order parameter is given by:

with Γ representing mobility of the phase. Eq. 6 may be evolved for various initial conditions, for example, to study the evolution of the phase separation of domains in the r < µ 2 /4 region.

With such conserved dynamics, we would typically expect Lifshitz-Slyosov domain evolution,

where domains grow as ∼ t 1/3 . 105 However, hydrodynamic effects may modify this scaling in more realistic scenarios. 106 The different phase-separated regions in a lipid vesicle may exhibit different preferred curvatures of the membrane, due to the particular geometry of the constituent lipid molecules. 107 Here, the shape of the membrane couples to the dynamics of φ, and we have to combine the free energy in Eq. (5) with elastic terms for the membrane and a coupling between φ and membrane curvature. Leibler and Andelman 108 showed that in the presence of such couplings, the line tension term, κ|∇φ| 2 /2, gets contributions from membrane curvature and can even change signs. When κ is driven to negative values, the quartic derivative term, |∇ 2 φ| 2 /2, must be included in the theory and the free energy, F, is now minimized by spatially modulated configurations. Microscopic models also reveal that a coupling to membrane curvature is sufficient to drive the surface tension term negative. 109 By including sign changes in κ, this makes the phase space of the theory in Eq. (5) much richer, and the various possibilities present a unified way of thinking about lipid membrane heterogeneity. 110 In the mean-field (ignoring thermal fluctuations), the phase portrait of the model is shown in Fig. 4 . Figure 4 : Schematic of the various phases described by the free energy in Eq. (5) for µ = 0. The phase boundaries are given in the single-mode mean-field approximation. 110 We see that when the gradient term κ < 0, it is possible to form an ordered modulated (patterned) phase and a disordered "microemulsion", with a characteristic wave number q 0 . Here we have shown possibilities for the phases on the surface of a vesicle, which introduces its own complications due to the finite spherical geometry. For example, the striped modulated phase shown has stripes terminating at the poles. Moreover, any of the modulated phases will have defects induced by the spherical topology.

When κ < 0, the free energy develops minima with configurations of φ(x) with non-zero Fourier modes. In particular, using a simple single-mode approximation, one can show that in the mean-field, the preferred wave number is |q| = q 0 = −κ/2 (see Eq. (5) have nanoscopic domains and are more likely to be in the disordered "microemulsion" phase instead of these highly ordered patterned phases. Note that we may incorporate dynamics by using an equation such as Eq. (6). In the case of a free energy with parameters corresponding to a modulated phase, the dynamics reduce to the so-called "phase field crystal". 115 The dynamics of the modulated phases include interesting cases such as, the formation of a foam after a rapid quench into the modulated phase. 116 Such foamy states appear to be relevant for pollen grain patterns, as well. 111 Foamy structures may also be observed in synthetic lipid vesicles with specific compositions. 117 If κ is large and negative, then we will be deep in the modulated phase/microemulsion regime and we can expand our free energy around the dominant Fourier modes with |q| = q 0 .

For a spherical vesicle, Fourier modes are inappropriate and one has to expand the field Figure 5 : (a) Mean-field phase diagram for the modulated phases with a fixed κ < 0 in Eq. (5) and a flat and infinite two-dimensional substrate. We see that the cubic term µ tunes between the striped phase (middle), the hexagonal phase (top), and the inverted hexagonal phase (bottom). When r > 0, we also find a microemulsion region, denoted by the yellow. (b) Modulated phases on a sphere have a more complex structure, since the pattern has to wrap the sphere 0 = q 0 R times, and has defects. We show the various possible shapes for small values of 0 . Note the wide range of shapes, including continuously varying "intermediate" states. In general, on the sphere the free energy landscape becomes much more complicated than for a flat, infinite substrate. The phase diagram is adapted from Radja et al. 111 Here, we have a rescaled cubic termμ ∝ µ. r is fixed to a negative value ensuring that we are always in a modulated phase.

is the location on the spherical membrane in spherical coordinates. We also have the usual spherical harmonics Y m (θ), with = 0, 1, 2, . . . the "total angular momentum" mode number and 18 J o u r n a l P r e -p r o o f m = − , − + 1, . . . , the azimuthal mode number. Then, we expect that the field has contributions primarily around the spherical harmonic modes with ≈ 0 ≈ q 0 R, with R the vesicle radius. This parameter will strongly influence the kinds of patterned phases that can form, as shown in Fig. 5 . We can rewrite the free energy in Eq. (5) on the sphere in the following (rescaled) Landau-Brazovskii 111,118 form:

where Υ 1 , 2 , 3 m 1 ,m 2 ,m 3 are the so-called Gaunt coefficients 119 coming from integrations of products of three spherical harmonics. We see here that the cubic and quartic terms in the thermodynamic potential will couple different spherical harmonic modes. Minimizing Eq. (7) over the set of coefficients c m yields a rich set of possibilities for modulated phases, some of which are illustrated in Fig. 5(b) . A free energy of this type is not only useful for understanding lipid vesicles and pollen grains, but also viral capsid formation. 120 We have spent some time considering the modulated phases (κ, r < 0 in Eq. (5)). However, as mentioned previously, lipid heterogeneities in living cells and in many synthetic lipid mixtures are best thought of as disordered, microemulsion phases. The main difficulty of this hypothesis is explaining the origin of the sign change of κ. However, one possibility is that differences in composition between lipid leaflets can induce such a sign change via a mechanism similar to spontaneous curvature. 121 This is plausible as living cells are known to maintain asymmetric lipid compositions on their inner and outer membrane leaflets. 122 In this phase, the order parameter remains, on average, zero ( φ = 0), but exhibits particular fluctuations with dominant contributions at the characteristic wavevectors with |q| = q 0 (or modes = 0 on the sphere), resulting in a structure factor S(q).

The structure factor, S(q), for the lipid membrane can be measured via a scattering (neutron or X-ray) experiment. 124 Small angle neutron scattering is particularly valuable as it provides better contrast to probe the lateral membrane heterogeneity, even when these heterogeneities are nanoscopic. 125, 126 To get good contrast on the lateral heterogeneity within the membrane, deuterated lipid mixtures may be used to mask one of the liquid phases, for example. A schematic of the idea is shown in Fig. 6(a) . Here, lipid vesicles are prepared with particular deuteration levels such that, at high temperatures when the lipids remain mixed the SLD of the acyl tails match the SLD of the surrounding fluid. Thus, the lipid vesicles become "invisible" to neutrons, as shown by the flat curves at high temperatures in Fig. 6(b) .

At lower temperatures, we have the liquid-liquid phase separation (or possibly microemulsion or modulated phase formation) and the SLDs of the liquid-ordered and liquid-disordered regions will be different, creating contrast for the neutron scattering as shown in Fig. 6(a) .

In this case, the neutron scattering will come from fluctuations in the lipid composition.

Therefore, it is a direct probe of our order parameter, φ(x). For scattering from lipid vesicles, the scattering intensity, I, is a probe of the fluctuations |c m | 2 of the spherical harmonic modes of φ(x). For a microemulsion phase, we expect that

where R is the vesicle radius and ξ the correlation length.

Such a phenomenological approach was used successfully to interpret scattering data of lipid vesicles in the presence of melatonin 123 -although a true microemulsion phase could not be established as the scattering data was also consistent with 0 = 0 (a regular phase-separated phase). Fits using the microemulsion theory are shown in Fig. 6(b) . Note, that this theory works well even when compared to a more microscopic model of domain configurations shown in Fig. 6(c) . In other words, the simple phenomenological free energy approach presented here provides a conceptual framework for understanding the scattering data and interpreting the wide range of phase behaviors observed for lateral lipid organization in cell membranes. Being near a phase transition allows for small changes in the environment to have a large effect on the appearance and size of rafts. One proposed scenario is that rafts may provide a buffering role in stabilizing membrane physiological properties across a range of temperatures. 44 Here, high-melting temperature raft lipids diffuse into the disordered phase as temperature increases, maintaining membrane bending rigidity and viscosity. It has also been theorized that cells vary their lipid composition to control the formation of rafts. 150 

The fluid mosaic model of the structure of cell membranes

Lateral phase separation in phospholipid membranes

Clusters in lipid bilayers and the interpretation of thermal effects in biological membranes

Domain formation in membranes with quenched protein obstacles: lateral heterogeneity and the connection to universality classes

Critical size dependence of domain formation observed in coarse-grained simulations of bilayers composed of ternary lipid mixtures

Fractal boundaries underpin the 2D melting of biomimetic rafts

Undulations drive domain registration from the two membrane leaflets

Relating domain size distribution to line tension and molecular dipole density in model cytoplasmic myelin lipid monolayers

Quantized symmetry of liquid monolayer domains

Line tension and interaction energies of membrane rafts calculated from lipid splay and tilt

Domain formation in membranes caused by lipid wetting of protein

Temperature dependence of structure, bending rigidity, and bilayer interactions of dioleoylphosphatidylcholine bilayers

Crossover from picosecond collective to single particle dynamics defines the mechanism of lateral lipid diffusion

Revealing the mechanism of passive transport in lipid bilayers via phonon-mediated nanometre-scale density fluctuations

Intrinsic curvature in normal and inverted lipid structures and in membranes

Lipid domain co-localization induced by membrane undulations. Biophys

Cholesterol flip-flop impacts domain registration in plasma membrane models

Effect of the structure of lipids favoring disordered domain formation on the stability of cholesterol-containing ordered domains (lipid rafts): identification of multiple raft-stabilization mechanisms

Polyunsaturated fatty acid-cholesterol interactions: domain formation in membranes

Molecular-level organization of saturated and polyunsaturated fatty acids in a phosphatidylcholine bilayer containing cholesterol

All n-3 PUFA are not the same: MD simulations reveal differences in membrane organization for EPA, DHA and DPA

Sphingomyelin analogs with branched Nacyl chains: the position of branching dramatically affects acyl chain order and sterol interactions in bilayer membranes

Undulations, steric interaction and cohesion of fluid membranes

Mechanical properties of nanoscopic lipid domains

Long-range interlayer alignment of intralayer domains in stacked lipid bilayers

Bending rigidities and interdomain forces in membranes with coexisting lipid domains

Subnanometer structure of an asymmetric model membrane: interleaflet coupling influences domain properties

Separation of liquid phases in giant vesicles of ternary mixtures of phospholipids and cholesterol

Domain stability in biomimetic membranes driven by lipid polyunsaturation

Investigation of phase transitions of lipids and lipid mixtures by sensitivity differential scanning calorimetry

Miscibility properties of binary phosphatidylcholine mixtures. A calorimetric study

Dilatometric study of binary mixtures of phosphatidylcholines

Small-angle neutron scattering study of lipid phase diagrams by the contrast variation method

Smoothed acyl chain orientational order parameter profiles in dimyristoylphosphatidylcholine-distearoylphosphatidylcholine mixtures: a 2H-NMR study

Thermotropic phase transitions of pure lipids in model membranes and their modifications by membrane proteins. Lipid-protein interactions

Fluid phase lipid areas and bilayer thicknesses of commonly used phosphatidylcholines as a function of temperature

Area per lipid and acyl length distributions in fluid phosphatidylcholines determined by 2H NMR spectroscopy

Lipid bilayer structure

Bilayer thickness mismatch controls domain size in model membranes

Cellular lipidomics

Lipidomics: coming to grips with lipid diversity

Understanding the diversity of membrane lipid composition

Raftlike mixtures of sphingomyelin and cholesterol investigated by solid-state 2H NMR spectroscopy

Hexagonal substructure and hydrogen bonding in liquid-ordered phases containing palmitoyl sphingomyelin

Cholesterol-sphingomyelin interactions: a molecular dynamics simulation study

Design and Synthesis of Sphingomyelin-Cholesterol Conjugates and Their Formation of Ordered Membranes

Sphingomyelin stereoisomers reveal that homophilic interactions cause nanodomain formation

Nanoscale membrane domain formation driven by cholesterol

Functional lipid pairs as building blocks of phase-separated membranes

Molecular organization in cholesterol-lecithin bilayers by x-ray and electron diffraction measurements

Combined influence of cholesterol and synthetic amphiphillic peptides upon bilayer thickness in model membranes

Structure of dipalmitoylphosphatidylcholine/cholesterol bilayer at low and high cholesterol concentrations: molecular dynamics simulation

Modulation of the bilayer thickness of exocytic pathway membranes by membrane proteins rather than cholesterol

Elastic deformation of membrane bilayers probed by deuterium NMR relaxation

Bending rigidity of SOPC membranes containing cholesterol

Entropy-driven tension and bending elasticity in condensedfluid membranes

Effect of cholesterol on the rigidity of saturated and unsaturated membranes: fluctuation and electrodeformation analysis of giant vesicles

Lipid miscibility and size increase of vesicles composed of two phosphatidylcholines

Configurational statistics of acyl chains in polyunsaturated lipid bilayers from deuterium NMR

Acyl chain conformations in phospholipid bilayers: a comparative study of docosahexaenoic acid and saturated fatty acids

Docosahexaenoic and eicosapentaenoic acids segregate differently between raft and nonraft domains

DHA modifies the size and composition of raftlike domains: a solid-state 2H NMR study

How polyunsaturated fatty acids modify molecular organization in membranes: insight from NMR studies of model systems

Cholesterol in bilayers with PUFA chains: doping with DMPC or POPC results in sterol reorientation and membrane-domain formation

Deuterium NMR of raft model membranes reveals domain-specific order profiles and compositional distribution

Lipid lateral diffusion in bilayers with phosphatidylcholine, sphingomyelin and cholesterol: An NMR study of dynamics and lateral phase separation

Characterization of the ternary mixture of sphingomyelin, POPC, and cholesterol: support for an inhomogeneous lipid distribution at high temperatures

Docosahexaenoic acid promotes micron scale liquid-ordered domains. A comparison study of docosahexaenoic versus oleic acid containing phosphatidylcholine in raft-like mixtures

Lowering line tension with high cholesterol content induces a transition from macroscopic to nanoscopic phase domains in model biomembranes

Cholesterol 36 for the interior of polyunsaturated lipid membranes

Cholesterol hydroxyl group is found to

Cholesterol is found to

Presence and role of midplane cholesterol in lipid bilayers containing registered or antiregistered phase domains

Push-pull mechanism for lipid raft formation

Push and pull forces in lipid raft formation: the push can be as important as the pull

Protein-driven lipid domain nucleation in biological membranes

Caveolins, a family of scaffolding proteins for organizing "preassembled signaling complexes" at the plasma membrane

The JIP family of MAPK scaffold proteins

Mechanism for targeting the A-kinase anchoring protein AKAP18δ to the membrane

Theory of dynamic critical phenomena

Critical fluctuations in plasma membrane vesicles

Critical Casimir forces in cellular membranes

Dynamic Simulations of Multicomponent Lipid Membranes over Long Length and Time Scales

The kinetics of precipitation from supersaturated solid solutions

Dynamic scaling in phase separation kinetics for quasi-two-dimensional membranes

Lipid Polymorphisms and Membrane Shape

Ordered and curved meso-structures in membranes and amphiphilic films

Competition between line tension and curvature stabilizes modulated phase patterns on the surface of giant unilamellar vesicles: A simulation study

Macroscopic Phase Separation, Modulated Phases, and Microemulsions: A Unified Picture of Rafts

pollen cell wall patterns form from modulated phases

Firstorder patterning transitions on a sphere as a router to cell morphology

Feigenson

Imaging coexisting fluid domains in biomembrane models coupling curvature and line tension

Modeling elasticity in crystal growth

Emergence of foams from the breakdown of the phase field crystal model

Phase diagram of a 4-component lipid mixture: DSPC/DOPC/POPC/chol

Phase diagrams of multicomponent lipid vesicles: Effects of finite size and spherical geometry

Angular Momentum in Quantum Mechanics

Orientational phase transitions and the assembly of viral capsids

Membrane heterogeneity: Manifestation of a curvature-induced microemulsion

Lateral organization, bilayer asymmetry, and inter-leaflet coupling of biological membranes

Deciphering Melatonin-Stabilized Phase Separation in Phospholipid Bilayers

Models for randomly distributed nanoscopic domains on spherical vesicles

Using small-angle neutron scattering to detect nanoscopic lipid domains

Domains on a Sphere: Neutron Scattering, Models, and Mathematical Formalism

Phase transition of an isotropic system to a nonuniform state

Unbiased quantitative proteomics of lipid rafts reveals high specificity for signaling factors

Enrichment of lck in lipid rafts regulates colocalized fyn activation and the initiation of proximal signals through TCRαβ

Cholesterol depletion delocalizes phosphatidylinositol bisphosphate and inhibits hormone-stimulated phosphatidylinositol turnover

Lipid rafts and signal transduction

Roles for lipid heterogeneity in immunoreceptor signaling

Hydrophobic mismatch sorts SNARE proteins into distinct membrane domains

Protein sorting by lipid phase-like domains supports emergent signaling function in B lymphocyte plasma membranes

Partitioning of lipidmodified monomeric GFPs into membrane microdomains of live cells

Jessup, W. Visualizing lipid structure and raft domains in living cells with two-photon microscopy

Large-scale fluid/fluid phase separation of proteins and lipids in giant plasma membrane vesicles

Elucidating membrane structure and protein behavior using giant plasma membrane vesicles

Helicobacter pylori lipids can form ordered membrane domains (rafts)

Direct observation of the nanoscale dynamics of membrane lipids in a living cell

Direct chemical evidence for sphingolipid domains in the plasma membranes of fibroblasts

Dynamic reorganization and correlation among lipid raft components

Lipid rafts: contentious only from simplistic standpoints

The mystery of membrane organization: composition, regulation and roles of lipid rafts

Membrane domains beyond the reach of microscopy

Molecular Picture of the Transient Nature of Lipid Rafts

Critical fluctuations in plasma membrane vesicles

Gratton, E. Lipid rafts reconstituted in model membranes

Characterization of cholesterolsphingomyelin domains and their dynamics in bilayer membranes

Triton promotes domain formation in lipid raft mixtures

Liquid general anesthetics lower critical temperatures in plasma membrane vesicles

Conditions that stabilize membrane domains also antagonize n-alcohol anesthesia

Docosahexaenoic acid domains: the ultimate non-raft membrane domain

Membrane lipid raft organization is uniquely modified by n-3 polyunsaturated fatty acids

Biological and pathophysiological roles of endproducts of DHA oxidation

Permeability of dimyristoyl phosphatidylcholine/dipalmitoyl phosphatidylcholine bilayer membranes with coexisting gel and liquid-crystalline phases

Line tension at lipid phase boundaries as driving force for HIV fusion peptide-mediated fusion

Mitochondria do not contain lipid rafts, and lipid rafts do not contain mitochondrial proteins

Biophysical and biochemical mechanisms by which dietary N-3 polyunsaturated fatty acids from fish oil disrupt membrane lipid rafts

Membrane raft microdomains mediate lateral assemblies required for HIV-1 infection

HIV-1 Gag protein can sense the cholesterol and acyl chain environment in model membranes

Comparative lipidomics analysis of HIV-1 particles and their producer cell membrane in different cell lines

Target membrane cholesterol modulates single influenza virus membrane fusion efficiency but not rate

Influenza virus hemagglutinin concentrates in lipid raft microdomains for efficient viral fusion

Sphingolipid and cholesterol dependence of alphavirus membrane fusion Lack of correlation with lipid raft formation in target liposomes

Tuning membrane phase separation using nonlipid amphiphiles

• Review article describing recent experimental and theoretical membrane lateral heterogeneity research

• Describes the static and dynamic physical concepts behind domain formation in model membranes

• Describes coarse-grained, phenomenological approaches that result in phases associated with lipid lateral heterogeneity