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The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of
lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins Vitamin A, A, Vitamin D, D, Vitamin E, E and Vitamin K, K), monoglycerides, diglycerides, phospholipids, and o ...
molecule A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioche ...
s. These membranes are flat sheets that form a continuous barrier around all cells. The
cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the cytoplasm, interior of all Cell (biology), cells from th ...
s of almost all
organisms In biology, an organism () is any life, living system that functions as an individual entity. All organisms are composed of cells (cell theory). Organisms are classified by taxonomy (biology), taxonomy into groups such as Multicellular o ...
and many
virus A virus is a wikt:submicroscopic, submicroscopic infectious agent that replicates only inside the living Cell (biology), cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and ...
es are made of a lipid bilayer, as are the
nuclear membrane The nuclear envelope, also known as the nuclear membrane, is made up of two lipid bilayer polar membrane, membranes that in eukaryotic cells surround the Cell nucleus, nucleus, which encloses the genome, genetic material. The nuclear envelope ...
surrounding the
cell nucleus The cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryote, eukaryotic cell (biology), cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as ma ...
, and membranes of the
membrane-bound organelle In cell biology, an organelle is a specialized subunit, usually within a cell (biology), cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as Organ (anatomy), organs are to the ...
s in the cell. The lipid bilayer is the barrier that keeps ions,
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metabo ...
s and other molecules where they are needed and prevents them from diffusing into areas where they should not be. Lipid bilayers are ideally suited to this role, even though they are only a few
nanometer file:EM Spectrum Properties edit.svg, 330px, Different lengths as in respect to the electromagnetic spectrum, measured by the metre and its derived scales. The nanometre is often used to express dimensions on an atomic scale and mostly in the Mol ...
s in width, because they are impermeable to most water-soluble (
hydrophilic A hydrophile is a molecule or other molecular entity that is intermolecular force, attracted to water molecules and tends to be dissolution (chemistry), dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clar ...
) molecules. Bilayers are particularly impermeable to ions, which allows cells to regulate salt concentrations and pH by transporting ions across their membranes using proteins called ion pumps. Biological bilayers are usually composed of
amphiphilic An amphiphile (from the Greek αμφις amphis, both, and φιλíα philia, love, friendship), or amphipath, is a chemical compound possessing both hydrophilic (''water-loving'', polar) and lipophilic (''fat-loving'') properties. Such a compoun ...
phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophile, hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an Alcohol (chemistry), alcohol residue (usually a glycerol mol ...
s that have a hydrophilic phosphate head and a
hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly intermolecular force, repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend t ...
tail consisting of two fatty acid chains. Phospholipids with certain head groups can alter the surface chemistry of a bilayer and can, for example, serve as signals as well as "anchors" for other molecules in the membranes of cells. Just like the heads, the tails of lipids can also affect membrane properties, for instance by determining the phase of the bilayer. The bilayer can adopt a solid gel phase state at lower temperatures but undergo
phase transition In chemistry, thermodynamics, and other related fields, a phase transition (or phase change) is the physical process of transition between one state of a medium and another. Commonly the term is used to refer to changes among the basic State of ...
to a fluid state at higher temperatures, and the chemical properties of the lipids' tails influence at which temperature this happens. The packing of lipids within the bilayer also affects its mechanical properties, including its resistance to stretching and bending. Many of these properties have been studied with the use of artificial "model" bilayers produced in a lab. Vesicles made by model bilayers have also been used clinically to deliver drugs. The structure of
biological membrane A biological membrane, biomembrane or cell membrane is a Semipermeable membrane, selectively permeable membrane that separates the interior of a Cell (biology), cell from the extracellular, external environment or creates intracellular compartmen ...
s typically includes several types of molecules in addition to the phospholipids comprising the bilayer. A particularly important example in animal cells is
cholesterol Cholesterol is any of a class of certain organic compound, organic molecules called lipids. It is a sterol (or chemical modification, modified steroid), a type of lipid. Cholesterol is biosynthesis, biosynthesized by all animal Cell (biology)# ...
, which helps strengthen the bilayer and decrease its permeability. Cholesterol also helps regulate the activity of certain
integral membrane protein An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All transmembrane protein, ''transmembrane proteins'' are IMPs, but not all IMPs are transmembrane proteins. ...
s. Integral membrane proteins function when incorporated into a lipid bilayer, and they are held tightly to the lipid bilayer with the help of an
annular lipid shell Annular lipids (also called shell lipids or boundary lipids) are a set of lipids or lipidic molecules which preferentially bind or stick to the surface of membrane proteins in biological cells. They constitute a layer, or an annulus/ shell, of lipid ...
. Because bilayers define the boundaries of the cell and its compartments, these membrane proteins are involved in many intra- and inter-cellular signaling processes. Certain kinds of membrane proteins are involved in the process of fusing two bilayers together. This fusion allows the joining of two distinct structures as in the
acrosome reaction During fertilization, a sperm must first fuse with the plasma membrane and then penetrate the female egg cell to fertilize it. Fusing to the egg cell usually causes little problem, whereas penetrating through the egg's hard shell or extracellul ...
during
fertilization Fertilisation or fertilization (see American and British English spelling differences#-ise, -ize (-isation, -ization), spelling differences), also known as generative fertilisation, syngamy and impregnation, is the fusion of gametes to give ...
of an
egg An egg is an organic vessel grown by an animal to carry a possibly fertilized egg cell (a zygote) and to incubate from it an embryo An embryo is an initial stage of development of a multicellular organism. In organisms that Sexual repr ...
by a
sperm Sperm is the male reproductive Cell (biology), cell, or gamete, in anisogamous forms of sexual reproduction (forms in which there is a larger, female reproductive cell and a smaller, male one). Animals produce motile sperm with a tail known as ...
, or the entry of a
virus A virus is a wikt:submicroscopic, submicroscopic infectious agent that replicates only inside the living Cell (biology), cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and ...
into a cell. Because lipid bilayers are fragile and invisible in a traditional microscope, they are a challenge to study. Experiments on bilayers often require advanced techniques like
electron microscopy An electron microscope is a microscope that uses a beam of accelerated electrons as a source of illumination. As the wavelength of an electron can be up to 100,000 times shorter than that of visible light photons, electron microscopes have a hi ...
and
atomic force microscopy Atomic force microscopy (AFM) or scanning force microscopy (SFM) is a very-high-resolution type of scanning probe microscopy (SPM), with demonstrated resolution on the order of fractions of a nanometer, more than 1000 times better than the diffr ...
.

# Structure and organization

When phospholipids are exposed to water, they self-assemble into a two-layered sheet with the hydrophobic tails pointing toward the center of the sheet. This arrangement results in two “leaflets” that are each a single molecular layer. The center of this bilayer contains almost no water and excludes molecules like
sugar Sugar is the generic name for Sweetness, sweet-tasting, soluble carbohydrates, many of which are used in food. Simple sugars, also called monosaccharides, include glucose, fructose, and galactose. Compound sugars, also called disaccharides o ...
s or salts that dissolve in water. The assembly process is driven by interactions between hydrophobic molecules (also called the
hydrophobic effect The hydrophobic effect is the observed tendency of nonpolar substances to aggregate in an aqueous solution and exclude water#Properties, water molecules. The word hydrophobic literally means "water-fearing", and it describes the Segregation in m ...
). An increase in interactions between hydrophobic molecules (causing clustering of hydrophobic regions) allows water molecules to bond more freely with each other, increasing the entropy of the system. This complex process includes
non-covalent interactions In chemistry, a non-covalent interaction differs from a covalent bond in that it does not involve the sharing of electrons, but rather involves more dispersed variations of electromagnetic interactions between molecules or within a molecule. The c ...
such as
van der Waals force In molecular physics, the van der Waals force is a distance-dependent interaction between atoms or molecules. Unlike ionic bond, ionic or covalent bonds, these attractions do not result from a Chemical bond, chemical electronic bond; they are c ...
s,
electrostatic Electrostatics is a branch of physics that studies electric charges at rest ( static electricity). Since classical times, it has been known that some materials, such as amber, attract lightweight particles after rubbing. The Greek word f ...
and
hydrogen bonds In chemistry Chemistry is the scientific study of the properties and behavior of matter. It is a natural science that covers the elements that make up matter to the compounds made of atoms, molecules and ions: their composition, str ...
.

## Cross section analysis

The lipid bilayer is very thin compared to its lateral dimensions. If a typical mammalian cell (diameter ~10 micrometers) were magnified to the size of a watermelon (~1 ft/30 cm), the lipid bilayer making up the
plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the cytoplasm, interior of all Cell (biology), cells from th ...
would be about as thick as a piece of office paper. Despite being only a few nanometers thick, the bilayer is composed of several distinct chemical regions across its cross-section. These regions and their interactions with the surrounding water have been characterized over the past several decades with
x-ray reflectometry X-ray reflectivity (sometimes known as X-ray specular reflectivity, X-ray reflectometry, or XRR) is a surface-sensitive analytical technique used in chemistry Chemistry is the scientific study of the properties and behavior of matter. It is ...
,
neutron scattering Neutron scattering, the irregular dispersal of free neutrons by matter, can refer to either the naturally occurring physical process itself or to the man-made experimental techniques that use the natural process for investigating materials. Th ...
and
nuclear magnetic resonance Nuclear magnetic resonance (NMR) is a physical phenomenon in which atomic nucleus, nuclei in a strong constant magnetic field are perturbed by a weak oscillating magnetic field (in the near and far field, near field) and respond by producing ...
techniques. The first region on either side of the bilayer is the hydrophilic headgroup. This portion of the membrane is completely hydrated and is typically around 0.8-0.9 nm thick. In
phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophile, hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an Alcohol (chemistry), alcohol residue (usually a glycerol mol ...
bilayers the
phosphate In chemistry, a phosphate is an anion, salt (chemistry), salt, functional group or ester derived from a phosphoric acids and phosphates, phosphoric acid. It most commonly means orthophosphate, a derivative of phosphoric acid, orthophosphoric a ...
group is located within this hydrated region, approximately 0.5 nm outside the hydrophobic core. In some cases, the hydrated region can extend much further, for instance in lipids with a large protein or long sugar chain grafted to the head. One common example of such a modification in nature is the
lipopolysaccharide Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the Bacterial ...
coat on a bacterial outer membrane, which helps retain a water layer around the
bacterium Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typically a few micrometr ...
to prevent dehydration. Next to the hydrated region is an intermediate region that is only partially hydrated. This boundary layer is approximately 0.3 nm thick. Within this short distance, the water concentration drops from 2M on the headgroup side to nearly zero on the tail (core) side. The hydrophobic core of the bilayer is typically 3-4 nm thick, but this value varies with chain length and chemistry. Core thickness also varies significantly with temperature, in particular near a phase transition.

## Asymmetry

In many naturally occurring bilayers, the compositions of the inner and outer membrane leaflets are different. In human
red blood cells Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek language, Greek ''erythros'' for "red" and ''k ...
, the inner (cytoplasmic) leaflet is composed mostly of
phosphatidylethanolamine Phosphatidylethanolamine (PE) is a class of phospholipids found in biological membranes. They are synthesized by the addition of cytidine diphosphate-ethanolamine to diglycerides, releasing cytidine monophosphate. S-Adenosyl methionine, ''S''-Ade ...
,
phosphatidylserine Phosphatidylserine (abbreviated Ptd-L-Ser or PS) is a phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophile, hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, join ...
and
phosphatidylinositol Phosphatidylinositol (or Inositol Phospholipid) consists of a family of lipids as illustrated on the right, where red is x, blue is y, and black is z, in the context of independent variation, a class of the Glycerophospholipid, phosphatidylglyceri ...
and its phosphorylated derivatives. By contrast, the outer (extracellular) leaflet is based on
phosphatidylcholine Phosphatidylcholines (PC) are a class of phospholipids that incorporate choline as a headgroup. They are a major component of biological membranes and can be easily obtained from a variety of readily available sources, such as egg yolk or soybean ...
,
sphingomyelin Sphingomyelin (SPH, ˌsfɪŋɡoˈmaɪəlɪn) is a type of sphingolipid found in animal cell membranes, especially in the membranous myelin sheath that surrounds some nerve cell axons. It usually consists of phosphocholine and ceramide, or a ethano ...
and a variety of glycolipids. In some cases, this asymmetry is based on where the lipids are made in the cell and reflects their initial orientation. The biological functions of lipid asymmetry are imperfectly understood, although it is clear that it is used in several different situations. For example, when a cell undergoes
apoptosis Apoptosis (from grc, wikt:ἀπόπτωσις, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemistry, Biochemical events lead to characteristic cell changes (Morp ...
, the phosphatidylserine — normally localised to the cytoplasmic leaflet — is transferred to the outer surface: There, it is recognised by a
macrophage Macrophages (abbreviated as MPhi, φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ...
that then actively scavenges the dying cell. Lipid asymmetry arises, at least in part, from the fact that most phospholipids are synthesised and initially inserted into the inner monolayer: those that constitute the outer monolayer are then transported from the inner monolayer by a class of enzymes called flippases. Other lipids, such as sphingomyelin, appear to be synthesised at the external leaflet. Flippases are members of a larger family of lipid transport molecules that also includes floppases, which transfer lipids in the opposite direction, and scramblases, which randomize lipid distribution across lipid bilayers (as in apoptotic cells). In any case, once lipid asymmetry is established, it does not normally dissipate quickly because spontaneous flip-flop of lipids between leaflets is extremely slow. It is possible to mimic this asymmetry in the laboratory in model bilayer systems. Certain types of very small artificial
vesicle Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane * Synaptic vesicle ; In human embryology * Vesicle (embryology), bulge-like features o ...
will automatically make themselves slightly asymmetric, although the mechanism by which this asymmetry is generated is very different from that in cells. By utilizing two different monolayers in Langmuir-Blodgett deposition or a combination of Langmuir-Blodgett and vesicle rupture deposition it is also possible to synthesize an asymmetric planar bilayer. This asymmetry may be lost over time as lipids in supported bilayers can be prone to flip-flop. Although, it has been reported that lipid flip-flop is slow compare to cholesterol and other smaller molecules. It has been reported that the organization and dynamics of the lipid monolayers in a bilayer are coupled. For example, introduction of obstructions in one monolayer can slow down the lateral diffusion in both monolayers. In addition, phase separation in one monolayer can also induce phase separation in other monolayer even when other monolayer can not phase separate by itself.

## Phases and phase transitions

At a given temperature a lipid bilayer can exist in either a liquid or a gel (solid) phase. All lipids have a characteristic temperature at which they transition (melt) from the gel to liquid phase. In both phases the lipid molecules are prevented from flip-flopping across the bilayer, but in liquid phase bilayers a given lipid will exchange locations with its neighbor millions of times a second. This
random walk In mathematics, a random walk is a random process that describes a path that consists of a succession of random steps on some Space (mathematics), mathematical space. An elementary example of a random walk is the random walk on the integer n ...
exchange allows lipid to diffuse and thus wander across the surface of the membrane. Unlike liquid phase bilayers, the lipids in a gel phase bilayer have less mobility. The phase behavior of lipid bilayers is determined largely by the strength of the attractive Van der Waals interactions between adjacent lipid molecules. Longer-tailed lipids have more area over which to interact, increasing the strength of this interaction and, as a consequence, decreasing the lipid mobility. Thus, at a given temperature, a short-tailed lipid will be more fluid than an otherwise identical long-tailed lipid. Transition temperature can also be affected by the degree of unsaturation of the lipid tails. An unsaturated
double bond In chemistry, a double bond is a covalent bond between two atoms involving four Electron pair bond, bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double ...
can produce a kink in the
alkane In organic chemistry Organic chemistry is a subdiscipline within chemistry involving the science, scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms tha ...
chain, disrupting the lipid packing. This disruption creates extra free space within the bilayer that allows additional flexibility in the adjacent chains. An example of this effect can be noted in everyday life as butter, which has a large percentage saturated fats, is solid at room temperature while vegetable oil, which is mostly unsaturated, is liquid. Most natural membranes are a complex mixture of different lipid molecules. If some of the components are liquid at a given temperature while others are in the gel phase, the two phases can coexist in spatially separated regions, rather like an iceberg floating in the ocean. This phase separation plays a critical role in biochemical phenomena because membrane components such as proteins can partition into one or the other phase and thus be locally concentrated or activated. One particularly important component of many mixed phase systems is
cholesterol Cholesterol is any of a class of certain organic compound, organic molecules called lipids. It is a sterol (or chemical modification, modified steroid), a type of lipid. Cholesterol is biosynthesis, biosynthesized by all animal Cell (biology)# ...
, which modulates bilayer permeability, mechanical strength, and biochemical interactions.

## Surface chemistry

While lipid tails primarily modulate bilayer phase behavior, it is the headgroup that determines the bilayer surface chemistry. Most natural bilayers are composed primarily of
phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophile, hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an Alcohol (chemistry), alcohol residue (usually a glycerol mol ...
s, but sphingolipids and
sterol Sterol is an organic compound with formula , whose molecule is derived from that of gonane by replacement of a hydrogen atom in position 3 by a hydroxyl group. It is therefore an alcohol (chemistry), alcohol of gonane. More generally, any compounds ...
s such as
cholesterol Cholesterol is any of a class of certain organic compound, organic molecules called lipids. It is a sterol (or chemical modification, modified steroid), a type of lipid. Cholesterol is biosynthesis, biosynthesized by all animal Cell (biology)# ...
are also important components. Of the phospholipids, the most common headgroup is
phosphatidylcholine Phosphatidylcholines (PC) are a class of phospholipids that incorporate choline as a headgroup. They are a major component of biological membranes and can be easily obtained from a variety of readily available sources, such as egg yolk or soybean ...
(PC), accounting for about half the phospholipids in most mammalian cells. PC is a
zwitterion In chemistry, a zwitterion ( ; ), also called an inner salt or dipolar ion, is a molecule that contains an equal number of positively- and negatively-charged functional groups. : With amino acids, for example, in solution a equilibrium chemistry, c ...
ic headgroup, as it has a negative charge on the phosphate group and a positive charge on the amine but, because these local charges balance, no net charge. Other headgroups are also present to varying degrees and can include
phosphatidylserine Phosphatidylserine (abbreviated Ptd-L-Ser or PS) is a phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophile, hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, join ...
(PS)
phosphatidylethanolamine Phosphatidylethanolamine (PE) is a class of phospholipids found in biological membranes. They are synthesized by the addition of cytidine diphosphate-ethanolamine to diglycerides, releasing cytidine monophosphate. S-Adenosyl methionine, ''S''-Ade ...
(PE) and
phosphatidylglycerol Phosphatidylglycerol is a glycerophospholipid found in pulmonary surfactant and in the plasma membrane where it directly activates lipid-gated ion channels. The general structure of phosphatidylglycerol consists of a L-glycerol 3-phosphate backbo ...
(PG). These alternate headgroups often confer specific biological functionality that is highly context-dependent. For instance, PS presence on the extracellular membrane face of
erythrocyte Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek language, Greek ''erythros'' for "red" and ''k ...
s is a marker of cell
apoptosis Apoptosis (from grc, wikt:ἀπόπτωσις, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemistry, Biochemical events lead to characteristic cell changes (Morp ...
, whereas PS in
growth plate The epiphyseal plate (or epiphysial plate, physis, or growth plate) is a hyaline cartilage plate in the metaphysis at each end of a long bone. It is the part of a long bone where new bone growth takes place; that is, the whole bone is alive, with ...
vesicles is necessary for the
nucleation In thermodynamics, nucleation is the first step in the formation of either a new Phase (matter), thermodynamic phase or Crystal structure, structure via self-assembly or self-organization within a substance or mixture. Nucleation is typically def ...
of
hydroxyapatite Hydroxyapatite, also called hydroxylapatite (HA), is a naturally occurring mineral form of calcium apatite with the Chemical formula, formula Ca5(PO4)3(OH), but it is usually written Ca10(PO4)6(OH)2 to denote that the Crystal structure, crysta ...
crystals and subsequent bone mineralization. Unlike PC, some of the other headgroups carry a net charge, which can alter the electrostatic interactions of small molecules with the bilayer.

# Biological roles

## Containment and separation

The primary role of the lipid bilayer in biology is to separate
aqueous An aqueous solution is a solution in which the solvent A solvent (s) (from the Latin language, Latin ''wikt:solvo#Latin, solvō'', "loosen, untie, solve") is a substance that dissolves a solute, resulting in a Solution (chemistry), solutio ...
compartments from their surroundings. Without some form of barrier delineating “self” from “non-self”, it is difficult to even define the concept of an organism or of life. This barrier takes the form of a lipid bilayer in all known life forms except for a few species of
archaea Archaea ( ; singular archaeon ) is a Domain (biology), domain of Unicellular organism, single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially Taxonomy (biology), classified as bacter ...
that utilize a specially adapted lipid monolayer. It has even been proposed that the very first form of life may have been a simple lipid vesicle with virtually its sole
biosynthetic Biosynthesis is a multi-step, enzyme-Catalysis, catalyzed process where substrate (chemistry), substrates are converted into more complex Product (chemistry), products in living organisms. In biosynthesis, simple Chemical compound, compounds are mo ...
capability being the production of more
phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophile, hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an Alcohol (chemistry), alcohol residue (usually a glycerol mol ...
s. The partitioning ability of the lipid bilayer is based on the fact that
hydrophilic A hydrophile is a molecule or other molecular entity that is intermolecular force, attracted to water molecules and tends to be dissolution (chemistry), dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clar ...
molecules cannot easily cross the
hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly intermolecular force, repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend t ...
bilayer core, as discussed in Transport across the bilayer below. The nucleus, mitochondria and chloroplasts have two lipid bilayers, while other sub-cellular structures are surrounded by a single lipid bilayer (such as the plasma membrane, endoplasmic reticula, Golgi apparatus and lysosomes). See
Organelle In cell biology, an organelle is a specialized subunit, usually within a cell (biology), cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as Organ (anatomy), organs are to the ...
.
Prokaryote A prokaryote () is a Unicellular organism, single-celled organism that lacks a cell nucleus, nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek language, Greek wikt:πρό#Ancient Greek, πρό (, 'before') a ...
s have only one lipid bilayer - the
cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the cytoplasm, interior of all Cell (biology), cells from th ...
(also known as the plasma membrane). Many prokaryotes also have a
cell wall A cell wall is a structural layer surrounding some types of cells, just outside the cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biolog ...
, but the cell wall is composed of
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metabo ...
s or long chain
carbohydrate In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may or may ...
s, not lipids. In contrast,
eukaryote Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the ...
s have a range of
organelle In cell biology, an organelle is a specialized subunit, usually within a cell (biology), cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as Organ (anatomy), organs are to the ...
s including the
nucleus Nucleus (plural, : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA ...
,
mitochondria A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which i ...
,
lysosome A lysosome () is a membrane-bound organelle found in many animal Cell (biology), cells. They are spherical Vesicle (biology and chemistry), vesicles that contain Hydrolysis, hydrolytic enzymes that can break down many kinds of biomolecules. A ly ...
s and
endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ...
. All of these sub-cellular compartments are surrounded by one or more lipid bilayers and, together, typically comprise the majority of the bilayer area present in the cell. In liver
hepatocyte A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass. These cells are involved in: * Protein biosynthesis, Protein synthesis * Storage protein, Protein storage * Transformation of carboh ...
s for example, the plasma membrane accounts for only two percent of the total bilayer area of the cell, whereas the endoplasmic reticulum contains more than fifty percent and the mitochondria a further thirty percent.

## Signaling

Probably the most familiar form of cellular signaling is
synaptic transmission Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to ...
, whereby a nerve impulse that has reached the end of one
neuron A neuron, neurone, or nerve cell is an membrane potential#Cell excitability, electrically excitable cell (biology), cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous ...
is conveyed to an adjacent neuron via the release of
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or mus ...
s. This transmission is made possible by the action of
synaptic vesicle In a neuron A neuron, neurone, or nerve cell is an membrane potential#Cell excitability, electrically excitable cell (biology), cell that communicates with other cells via specialized connections called synapses. The neuron is the main compon ...
s which are, inside the cell, loaded with the neurotransmitters to be released later. These loaded vesicles fuse with the cell membrane at the pre-synaptic terminal and their contents are released into the space outside the cell. The contents then diffuse across the synapse to the post-synaptic terminal. Lipid bilayers are also involved in signal transduction through their role as the home of
integral membrane protein An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All transmembrane protein, ''transmembrane proteins'' are IMPs, but not all IMPs are transmembrane proteins. ...
s. This is an extremely broad and important class of biomolecule. It is estimated that up to a third of the human
proteome The proteome is the entire set of protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, ...
are membrane proteins. Some of these proteins are linked to the exterior of the cell membrane. An example of this is the
CD59 CD59 glycoprotein, also known as MAC-inhibitory protein (MAC-IP), membrane inhibitor of reactive lysis (MIRL), or protectin, is a protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino ac ...
protein, which identifies cells as “self” and thus inhibits their destruction by the immune system. The
HIV The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause AIDS, acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the ...
immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as Tumor immunology, cancer cells and objects such ...
in part by grafting these proteins from the host membrane onto its own surface. Alternatively, some membrane proteins penetrate all the way through the bilayer and serve to relay individual signal events from the outside to the inside of the cell. The most common class of this type of protein is the
G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of protein family, evolution ...
(GPCR). GPCRs are responsible for much of the cell's ability to sense its surroundings and, because of this important role, approximately 40% of all modern drugs are targeted at GPCRs. In addition to protein- and solution-mediated processes, it is also possible for lipid bilayers to participate directly in signaling. A classic example of this is
phosphatidylserine Phosphatidylserine (abbreviated Ptd-L-Ser or PS) is a phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophile, hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, join ...
-triggered
phagocytosis Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis i ...
. Normally, phosphatidylserine is asymmetrically distributed in the cell membrane and is present only on the interior side. During programmed cell death a protein called a scramblase equilibrates this distribution, displaying phosphatidylserine on the extracellular bilayer face. The presence of phosphatidylserine then triggers phagocytosis to remove the dead or dying cell.

# Characterization methods

The lipid bilayer is a very difficult structure to study because it is so thin and fragile. In spite of these limitations dozens of techniques have been developed over the last seventy years to allow investigations of its structure and function.

## Electrical measurements

Electrical measurements are a straightforward way to characterize an important function of a bilayer: its ability to segregate and prevent the flow of ions in solution. By applying a voltage across the bilayer and measuring the resulting current, the resistance of the bilayer is determined. This resistance is typically quite high (108 Ohm-cm2 or more) since the hydrophobic core is impermeable to charged species. The presence of even a few nanometer-scale holes results in a dramatic increase in current. The sensitivity of this system is such that even the activity of single
ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by Gating (electrophysiol ...
s can be resolved.

## Fluorescence microscopy

A lipid bilayer cannot be seen with a traditional microscope, because it is too thin, so researchers often use
fluorescence microscopy A fluorescence microscope is an optical microscope that uses fluorescence instead of, or in addition to, scattering, reflection (physics), reflection, and attenuation or absorption (electromagnetic radiation), absorption, to study the propertie ...
. A sample is excited with one wavelength of light and observed in another, so that only fluorescent molecules with a matching excitation and emission profile will be seen. A natural lipid bilayer is not fluorescent, so at least one fluorescent dye needs to be attached to some of the molecules in the bilayer. Resolution is usually limited to a few hundred nanometers, which is unfortunately much larger than the thickness of a lipid bilayer.

## Electron microscopy

Electron microscopy An electron microscope is a microscope that uses a beam of accelerated electrons as a source of illumination. As the wavelength of an electron can be up to 100,000 times shorter than that of visible light photons, electron microscopes have a hi ...
offers a higher resolution image. In an
electron microscope An electron microscope is a microscope that uses a beam of accelerated electrons as a source of illumination. As the wavelength of an electron can be up to 100,000 times shorter than that of visible light photons, electron microscopes have a hi ...
, a beam of focused
electron The electron ( or ) is a subatomic particle with a negative one elementary charge, elementary electric charge. Electrons belong to the first generation (particle physics), generation of the lepton particle family, and are generally thought t ...
s interacts with the sample rather than a beam of light as in traditional microscopy. In conjunction with rapid freezing techniques, electron microscopy has also been used to study the mechanisms of inter- and intracellular transport, for instance in demonstrating that exocytotic vesicles are the means of chemical release at
synapse In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell. Synapses are essential to the transmission of nervous impulses from ...
s.

## Nuclear magnetic resonance spectroscopy

31P- NMR(nuclear magnetic resonance) spectroscopy is widely used for studies of phospholipid bilayers and biological membranes in native conditions. The analysis of 31P-NMR spectra of lipids could provide a wide range of information about lipid bilayer packing, phase transitions (gel phase, physiological liquid crystal phase, ripple phases, non bilayer phases), lipid head group orientation/dynamics, and elastic properties of pure lipid bilayer and as a result of binding of proteins and other biomolecules.

## Atomic force microscopy

A new method to study lipid bilayers is
Atomic force microscopy Atomic force microscopy (AFM) or scanning force microscopy (SFM) is a very-high-resolution type of scanning probe microscopy (SPM), with demonstrated resolution on the order of fractions of a nanometer, more than 1000 times better than the diffr ...
(AFM). Rather than using a beam of light or particles, a very small sharpened tip scans the surface by making physical contact with the bilayer and moving across it, like a record player needle. AFM is a promising technique because it has the potential to image with nanometer resolution at room temperature and even under water or physiological buffer, conditions necessary for natural bilayer behavior. Utilizing this capability, AFM has been used to examine dynamic bilayer behavior including the formation of transmembrane pores (holes) and phase transitions in supported bilayers. Another advantage is that AFM does not require fluorescent or isotopic labeling of the lipids, since the probe tip interacts mechanically with the bilayer surface. Because of this, the same scan can image both lipids and associated proteins, sometimes even with single-molecule resolution. AFM can also probe the mechanical nature of lipid bilayers.

## Dual polarisation interferometry

Lipid bilayers exhibit high levels of
birefringence Birefringence is the optics, optical property of a material having a refractive index that depends on the Polarization (waves), polarization and propagation direction of light. These optically anisotropic materials are said to be birefringent (or ...
where the refractive index in the plane of the bilayer differs from that perpendicular by as much as 0.1
refractive index In optics, the refractive index (or refraction index) of an optical medium is a dimensionless number that gives the indication of the light bending ability of that medium. The refractive index determines how much the path of light is bent, or ...
units. This has been used to characterise the degree of order and disruption in bilayers using
dual polarisation interferometry Dual-polarization interferometry (DPI) is an analytical technique that probes molecular layers adsorbed to the surface of a Waveguide (optics), waveguide using the evanescent wave of a laser beam. It is used to measure the conformational change ...
to understand mechanisms of protein interaction.

## Quantum chemical calculations

Lipid bilayers are complicated molecular systems with many degrees of freedom. Thus, atomistic simulation of membrane and in particular
ab initio ''Ab initio'' ( ) is a Latin term meaning "from the beginning" and is derived from the Latin ''ab'' ("from") + ''initio'', ablative case, ablative grammatical number, singular of ''initium'' ("beginning"). Etymology Circa 1600, from Latin, liter ...
calculations of its properties is difficult and computationally expensive. Quantum chemical calculations has recently been successfully performed to estimate
dipole In physics, a dipole () is an electromagnetic phenomenon which occurs in two ways: *An electric dipole moment, electric dipole deals with the separation of the positive and negative electric charges found in any electromagnetic system. A simple ...
and
quadrupole A quadrupole or quadrapole is one of a sequence of configurations of things like electric charge or current, or gravitational mass that can exist in ideal form, but it is usually just part of a multipole expansion of a more complex structure refl ...
moments of lipid membranes.

# Transport across the bilayer

## Passive diffusion

Most polar molecules have low solubility in the
hydrocarbon In organic chemistry, a hydrocarbon is an organic compound consisting entirely of hydrogen and carbon. Hydrocarbons are examples of group 14 hydrides. Hydrocarbons are generally colourless and Hydrophobe, hydrophobic, and their odors are usuall ...
core of a lipid bilayer and, as a consequence, have low permeability coefficients across the bilayer. This effect is particularly pronounced for charged species, which have even lower permeability coefficients than neutral polar molecules.
Anion An ion () is an atom or molecule with a net electric charge, electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be po ...
s typically have a higher rate of diffusion through bilayers than
cation An ion () is an atom or molecule with a net electric charge, electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be po ...
s. Compared to ions, water molecules actually have a relatively large permeability through the bilayer, as evidenced by osmotic swelling. When a cell or vesicle with a high interior salt concentration is placed in a solution with a low salt concentration it will swell and eventually burst. Such a result would not be observed unless water was able to pass through the bilayer with relative ease. The anomalously large permeability of water through bilayers is still not completely understood and continues to be the subject of active debate. Small uncharged apolar molecules diffuse through lipid bilayers many orders of magnitude faster than ions or water. This applies both to fats and organic solvents like
chloroform Chloroform, or trichloromethane, is an organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon chemical bond, bonds. Due to carbon's ability to Catenation, catenate ...
and
ether In organic chemistry, ethers are a class of organic compound, compounds that contain an ether functional group, group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl o ...
. Regardless of their polar character larger molecules diffuse more slowly across lipid bilayers than small molecules.

## Ion pumps and channels

Two special classes of protein deal with the ionic gradients found across cellular and sub-cellular membranes in nature-
ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by Gating (electrophysiol ...
s and ion pumps. Both pumps and channels are
integral membrane protein An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All transmembrane protein, ''transmembrane proteins'' are IMPs, but not all IMPs are transmembrane proteins. ...
s that pass through the bilayer, but their roles are quite different. Ion pumps are the proteins that build and maintain the chemical gradients by utilizing an external energy source to move ions against the concentration gradient to an area of higher
chemical potential In thermodynamics, the chemical potential of a Chemical specie, species is the energy that can be absorbed or released due to a change of the particle number of the given species, e.g. in a chemical reaction or phase transition. The chemical potent ...
. The energy source can be ATP, as is the case for the Na+-K+ ATPase. Alternatively, the energy source can be another chemical gradient already in place, as in the Ca2+/Na+ antiporter. It is through the action of ion pumps that cells are able to regulate pH via the pumping of protons. In contrast to ion pumps, ion channels do not build chemical gradients but rather dissipate them in order to perform work or send a signal. Probably the most familiar and best studied example is the voltage-gated Na+ channel, which allows conduction of an
action potential An action potential occurs when the membrane potential of a specific Cell (biology), cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of ...
along
neuron A neuron, neurone, or nerve cell is an membrane potential#Cell excitability, electrically excitable cell (biology), cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous ...
s. All ion pumps have some sort of trigger or “gating” mechanism. In the previous example it was electrical bias, but other channels can be activated by binding a molecular agonist or through a conformational change in another nearby protein.

## Endocytosis and exocytosis

Some molecules or particles are too large or too hydrophilic to pass through a lipid bilayer. Other molecules could pass through the bilayer but must be transported rapidly in such large numbers that channel-type transport is impractical. In both cases, these types of cargo can be moved across the cell membrane through fusion or budding of vesicles. When a vesicle is produced inside the cell and fuses with the plasma membrane to release its contents into the extracellular space, this process is known as exocytosis. In the reverse process, a region of the cell membrane will dimple inwards and eventually pinch off, enclosing a portion of the extracellular fluid to transport it into the cell. Endocytosis and exocytosis rely on very different molecular machinery to function, but the two processes are intimately linked and could not work without each other. The primary mechanism of this interdependence is the large amount of lipid material involved. In a typical cell, an area of bilayer equivalent to the entire plasma membrane will travel through the endocytosis/exocytosis cycle in about half an hour. If these two processes were not balancing each other, the cell would either balloon outward to an unmanageable size or completely deplete its plasma membrane within a short time. Exocytosis in prokaryotes: Membrane vesicular
exocytosis Exocytosis () is a form of active transport and solvent drag, bulk transport in which a cell transports molecules (e.g., neurotransmitters and proteins) out of the cell (''wikt:ex-#Prefix, exo-'' + ''cytosis''). As an active transport mechanism, ...
, popularly known as
membrane vesicle trafficking Membrane vesicle Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane * Synaptic vesicle ; In human embryology * Vesicle (embryology), bulg ...
, a Nobel prize-winning (year, 2013) process, is traditionally regarded as a prerogative of
eukaryotic Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the ...
cells. This ''myth'' was however broken with the revelation that nanovesicles, popularly known as
bacterial outer membrane vesicles Bacterial outer membrane vesicles (OMVs) are vesicles of lipids Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins Vitamin A, A, Vitamin D, D, Vitamin E, E an ...
, released by
gram-negative Gram-negative bacteria are bacteria that do not retain the Crystal violet, crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidogly ...
microbes, translocate bacterial signal molecules to host or target cells to carry out multiple processes in favour of the secreting microbe e.g., in ''host cell invasion'' and microbe-environment interactions, in general.

## Electroporation

Electroporation is the rapid increase in bilayer permeability induced by the application of a large artificial electric field across the membrane. Experimentally, electroporation is used to introduce hydrophilic molecules into cells. It is a particularly useful technique for large highly charged molecules such as DNA, which would never passively diffuse across the hydrophobic bilayer core. Because of this, electroporation is one of the key methods of
transfection Transfection is the process of deliberately introducing naked or purified nucleic acids into Eukaryote, eukaryotic Cell (biology), cells. It may also refer to other methods and cell types, although other terms are often preferred: "transformation ...
as well as bacterial transformation. It has even been proposed that electroporation resulting from
lightning Lightning is a naturally occurring electrostatic discharge during which two electric charge, electrically charged regions, both in the atmosphere or with one on the land, ground, temporarily neutralize themselves, causing the instantaneous ...
strikes could be a mechanism of natural
horizontal gene transfer Horizontal gene transfer (HGT) or lateral gene transfer (LGT) is the movement of genetic material between Unicellular organism, unicellular and/or multicellular organisms other than by the ("vertical") transmission of DNA from parent to offsprin ...
. This increase in permeability primarily affects transport of ions and other hydrated species, indicating that the mechanism is the creation of nm-scale water-filled holes in the membrane. Although electroporation and
dielectric breakdown Electrical breakdown or dielectric breakdown is a process that occurs when an electrical insulating material, subjected to a high enough voltage Voltage, also known as electric pressure, electric tension, or (electric) potential difference ...
both result from application of an electric field, the mechanisms involved are fundamentally different. In dielectric breakdown the barrier material is ionized, creating a conductive pathway. The material alteration is thus chemical in nature. In contrast, during electroporation the lipid molecules are not chemically altered but simply shift position, opening up a pore that acts as the conductive pathway through the bilayer as it is filled with water.

# Mechanics

Lipid bilayers are large enough structures to have some of the mechanical properties of liquids or solids. The area compression modulus Ka, bending modulus Kb, and edge energy $\Lambda$, can be used to describe them. Solid lipid bilayers also have a
shear modulus In materials science, shear modulus or modulus of rigidity, denoted by ''G'', or sometimes ''S'' or ''μ'', is a measure of the Elasticity (physics), elastic shear stiffness of a material and is defined as the ratio of shear stress to the shear s ...
, but like any liquid, the shear modulus is zero for fluid bilayers. These mechanical properties affect how the membrane functions. Ka and Kb affect the ability of proteins and small molecules to insert into the bilayer, and bilayer mechanical properties have been shown to alter the function of mechanically activated ion channels. Bilayer mechanical properties also govern what types of stress a cell can withstand without tearing. Although lipid bilayers can easily bend, most cannot stretch more than a few percent before rupturing. As discussed in the Structure and organization section, the hydrophobic attraction of lipid tails in water is the primary force holding lipid bilayers together. Thus, the elastic modulus of the bilayer is primarily determined by how much extra area is exposed to water when the lipid molecules are stretched apart. It is not surprising given this understanding of the forces involved that studies have shown that Ka varies strongly with
osmotic pressure Osmotic pressure is the minimum pressure which needs to be applied to a Solution (chemistry), solution to prevent the inward flow of its pure solvent across a semipermeable membrane. It is also defined as the measure of the tendency of a soluti ...
but only weakly with tail length and unsaturation. Because the forces involved are so small, it is difficult to experimentally determine Ka. Most techniques require sophisticated microscopy and very sensitive measurement equipment. In contrast to Ka, which is a measure of how much energy is needed to stretch the bilayer, Kb is a measure of how much energy is needed to bend or flex the bilayer. Formally, bending modulus is defined as the energy required to deform a membrane from its intrinsic curvature to some other curvature. Intrinsic curvature is defined by the ratio of the diameter of the head group to that of the tail group. For two-tailed PC lipids, this ratio is nearly one so the intrinsic curvature is nearly zero. If a particular lipid has too large a deviation from zero intrinsic curvature it will not form a bilayer and will instead form other phases such as
micelle A micelle () or micella () (plural micelles or micellae, respectively) is an aggregate (or supramolecular assembly) of surfactant amphipathic lipid molecules dispersed in a liquid, forming a colloid, colloidal suspension (also known as associat ...
s or inverted micelles. Addition of ''small hydrophilic molecules'' like ''sucrose'' into mixed lipid ''lamellar liposomes'' made from galactolipid-rich thylakoid membranes destabilises bilayers into micellar phase. Typically, Kb is not measured experimentally but rather is calculated from measurements of Ka and bilayer thickness, since the three parameters are related. $\Lambda$ is a measure of how much energy it takes to expose a bilayer edge to water by tearing the bilayer or creating a hole in it. The origin of this energy is the fact that creating such an interface exposes some of the lipid tails to water, but the exact orientation of these border lipids is unknown. There is some evidence that both hydrophobic (tails straight) and hydrophilic (heads curved around) pores can coexist.

# Fusion

Fusion is the process by which two lipid bilayers merge, resulting in one connected structure. If this fusion proceeds completely through both leaflets of both bilayers, a water-filled bridge is formed and the solutions contained by the bilayers can mix. Alternatively, if only one leaflet from each bilayer is involved in the fusion process, the bilayers are said to be hemifused. Fusion is involved in many cellular processes, in particular in
eukaryote Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the ...
s, since the eukaryotic cell is extensively sub-divided by lipid bilayer membranes.
Exocytosis Exocytosis () is a form of active transport and solvent drag, bulk transport in which a cell transports molecules (e.g., neurotransmitters and proteins) out of the cell (''wikt:ex-#Prefix, exo-'' + ''cytosis''). As an active transport mechanism, ...
,
fertilization Fertilisation or fertilization (see American and British English spelling differences#-ise, -ize (-isation, -ization), spelling differences), also known as generative fertilisation, syngamy and impregnation, is the fusion of gametes to give ...
of an
egg An egg is an organic vessel grown by an animal to carry a possibly fertilized egg cell (a zygote) and to incubate from it an embryo An embryo is an initial stage of development of a multicellular organism. In organisms that Sexual repr ...
by sperm activation, and transport of waste products to the lysozome are a few of the many eukaryotic processes that rely on some form of fusion. Even the entry of pathogens can be governed by fusion, as many bilayer-coated
virus A virus is a wikt:submicroscopic, submicroscopic infectious agent that replicates only inside the living Cell (biology), cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and ...
es have dedicated fusion proteins to gain entry into the host cell. There are four fundamental steps in the fusion process. First, the involved membranes must aggregate, approaching each other to within several nanometers. Second, the two bilayers must come into very close contact (within a few angstroms). To achieve this close contact, the two surfaces must become at least partially dehydrated, as the bound surface water normally present causes bilayers to strongly repel. The presence of ions, in particular divalent cations like magnesium and calcium, strongly affects this step. One of the critical roles of calcium in the body is regulating membrane fusion. Third, a destabilization must form at one point between the two bilayers, locally distorting their structures. The exact nature of this distortion is not known. One theory is that a highly curved "stalk" must form between the two bilayers. Proponents of this theory believe that it explains why phosphatidylethanolamine, a highly curved lipid, promotes fusion. Finally, in the last step of fusion, this point defect grows and the components of the two bilayers mix and diffuse away from the site of contact. The situation is further complicated when considering fusion ''in vivo'' since biological fusion is almost always regulated by the action of membrane-associated proteins. The first of these proteins to be studied were the viral fusion proteins, which allow an enveloped
virus A virus is a wikt:submicroscopic, submicroscopic infectious agent that replicates only inside the living Cell (biology), cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and ...
to insert its genetic material into the host cell (enveloped viruses are those surrounded by a lipid bilayer; some others have only a protein coat).
Eukaryotic Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the ...
cells also use fusion proteins, the best-studied of which are the SNAREs. SNARE proteins are used to direct all vesicular intracellular trafficking. Despite years of study, much is still unknown about the function of this protein class. In fact, there is still an active debate regarding whether SNAREs are linked to early docking or participate later in the fusion process by facilitating hemifusion. In studies of molecular and cellular biology it is often desirable to artificially induce fusion. The addition of
polyethylene glycol Polyethylene glycol (PEG; ) is a polyether compound derived from petroleum Petroleum, also known as crude oil, or simply oil, is a naturally occurring yellowish-black liquid mixture of mainly hydrocarbons, and is found in geological for ...
(PEG) causes fusion without significant aggregation or biochemical disruption. This procedure is now used extensively, for example by fusing
B-cell B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
s with
myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibody, antibodies. Often, no symptoms are noticed initially. As it progresses, bone p ...
cells. The resulting “ hybridoma” from this combination expresses a desired
antibody An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and Viral disease, viruses. The antibody recognizes a unique m ...
as determined by the B-cell involved, but is immortalized due to the melanoma component. Fusion can also be artificially induced through
electroporation Electroporation, or electropermeabilization, is a microbiology technique in which an electrical field is applied to cells in order to increase the permeability of the cell membrane, allowing chemicals, drugs, electrode arrays or DNA to be introduc ...
in a process known as electrofusion. It is believed that this phenomenon results from the energetically active edges formed during electroporation, which can act as the local defect point to nucleate stalk growth between two bilayers.

# Model systems

Lipid bilayers can be created artificially in the lab to allow researchers to perform experiments that cannot be done with natural bilayers. They can also be used in the field of
Synthetic Biology Synthetic biology (SynBio) is a multidisciplinary area of research that seeks to create new biological parts, devices, and systems, or to redesign systems that are already found in nature. It is a branch of science that encompasses a broad ran ...
, to define the boundaries of
artificial cell An artificial cell, synthetic cell or minimal cell is an engineered particle that mimics one or many functions of a Cell (biology), biological cell. Often, artificial cells are biological or polymeric membranes which enclose biologically active mat ...
s. These synthetic systems are called model lipid bilayers. There are many different types of model bilayers, each having experimental advantages and disadvantages. They can be made with either synthetic or natural lipids. Among the most common model systems are: * Black lipid membranes (BLM) * Supported lipid bilayers (SLB) * Tethered Bilayer Lipid Membranes (t-BLM) * Vesicles * Droplet Interface Bilayers (DIBs)

# Commercial applications

To date, the most successful commercial application of lipid bilayers has been the use of
liposome A liposome is a small artificial Vesicle (biology and chemistry), vesicle, spherical in shape, having at least one lipid bilayer. Due to their hydrophobicity and/or hydrophilicity, biocompatibility, particle size and many other properties, lipo ...
s for drug delivery, especially for cancer treatment. (Note- the term “liposome” is in essence synonymous with “
vesicle Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane * Synaptic vesicle ; In human embryology * Vesicle (embryology), bulge-like features o ...
” except that vesicle is a general term for the structure whereas liposome refers to only artificial not natural vesicles) The basic idea of liposomal drug delivery is that the drug is encapsulated in solution inside the liposome then injected into the patient. These drug-loaded liposomes travel through the system until they bind at the target site and rupture, releasing the drug. In theory, liposomes should make an ideal drug delivery system since they can isolate nearly any hydrophilic drug, can be grafted with molecules to target specific tissues and can be relatively non-toxic since the body possesses biochemical pathways for degrading lipids. The first generation of drug delivery liposomes had a simple lipid composition and suffered from several limitations. Circulation in the bloodstream was extremely limited due to both
renal The kidneys are two reddish-brown bean-shaped organs In biology, an organ is a collection of Tissue (biology), tissues joined in a structural unit to serve a common function. In the biological organization, hierarchy of life, an organ lies ...
clearing and
phagocytosis Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis i ...
. Refinement of the lipid composition to tune fluidity, surface charge density, and surface hydration resulted in vesicles that adsorb fewer proteins from serum and thus are less readily recognized by the
immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as Tumor immunology, cancer cells and objects such ...
. The most significant advance in this area was the grafting of
polyethylene glycol Polyethylene glycol (PEG; ) is a polyether compound derived from petroleum Petroleum, also known as crude oil, or simply oil, is a naturally occurring yellowish-black liquid mixture of mainly hydrocarbons, and is found in geological for ...
(PEG) onto the liposome surface to produce “stealth” vesicles, which circulate over long times without immune or renal clearing. The first stealth liposomes were passively targeted at
tumor A neoplasm () is a type of abnormal and excessive growth of tissue (biology), tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tiss ...
tissues. Because tumors induce rapid and uncontrolled
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the circulatory system, vasculature by processes of spr ...
they are especially “leaky” and allow liposomes to exit the bloodstream at a much higher rate than normal tissue would. More recently work has been undertaken to graft
antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform ...
or other molecular markers onto the liposome surface in the hope of actively binding them to a specific cell or tissue type. Some examples of this approach are already in clinical trials. Another potential application of lipid bilayers is the field of
biosensor A biosensor is an analytical device, used for the detection of a chemical substance, that combines a biological component with a physical chemistry, physicochemical detector. The ''sensitive biological element'', e.g. tissue, microorganisms, or ...
s. Since the lipid bilayer is the barrier between the interior and exterior of the cell, it is also the site of extensive signal transduction. Researchers over the years have tried to harness this potential to develop a bilayer-based device for clinical diagnosis or bioterrorism detection. Progress has been slow in this area and, although a few companies have developed automated lipid-based detection systems, they are still targeted at the research community. These include Biacore (now GE Healthcare Life Sciences), which offers a disposable chip for utilizing lipid bilayers in studies of binding kinetics
Biacore Inc. Retrieved Feb 12, 2009.
and Nanion Inc., which has developed an Planar patch clamp, automated patch clamping system. Other, more exotic applications are also being pursued such as the use of lipid bilayer membrane pores for
DNA sequencing DNA sequencing is the process of determining the nucleic acid sequence – the order of nucleotides in DNA. It includes any method or technology that is used to determine the order of the four bases: adenine, guanine, cytosine, and thymine. The ...
by Oxford Nanolabs. To date, this technology has not proven commercially viable. A supported lipid bilayer (SLB) as described above has achieved commercial success as a screening technique to measure the permeability of drugs. This parallel artificial membrane permeability assay
PAMPA The Pampas (from the qu, pampa, meaning "plain") are fertile South American low grasslands that cover more than and include the Argentine Provinces of Argentina, provinces of Buenos Aires Province, Buenos Aires, La Pampa Province, La Pampa, ...
technique measures the permeability across specifically formulated lipid cocktail(s) found to be highly correlated with Caco-2 cultures, the
gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organ (biology), organs of the digestive syste ...
,
blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...
and skin.

# History

By the early twentieth century scientists had come to believe that cells are surrounded by a thin oil-like barrier, but the structural nature of this membrane was not known. Two experiments in 1925 laid the groundwork to fill in this gap. By measuring the
capacitance Capacitance is the capability of a material object or device to store electric charge. It is measured by the change in charge in response to a difference in electric potential, expressed as the ratio of those quantities. Commonly recognized are ...
of
erythrocyte Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek language, Greek ''erythros'' for "red" and ''k ...
solutions, Hugo Fricke determined that the cell membrane was 3.3 nm thick. Although the results of this experiment were accurate, Fricke misinterpreted the data to mean that the cell membrane is a single molecular layer. Prof. Dr. Evert Gorter (1881–1954) and F. Grendel of Leiden University approached the problem from a different perspective, spreading the erythrocyte lipids as a monolayer on a Langmuir-Blodgett trough. When they compared the area of the monolayer to the surface area of the cells, they found a ratio of two to one. Later analyses showed several errors and incorrect assumptions with this experiment but, serendipitously, these errors canceled out and from this flawed data Gorter and Grendel drew the correct conclusion- that the cell membrane is a lipid bilayer. This theory was confirmed through the use of
electron microscopy An electron microscope is a microscope that uses a beam of accelerated electrons as a source of illumination. As the wavelength of an electron can be up to 100,000 times shorter than that of visible light photons, electron microscopes have a hi ...
in the late 1950s. Although he did not publish the first electron microscopy study of lipid bilayers J. David Robertson was the first to assert that the two dark electron-dense bands were the headgroups and associated proteins of two apposed lipid monolayers. In this body of work, Robertson put forward the concept of the “unit membrane.” This was the first time the bilayer structure had been universally assigned to all cell membranes as well as
organelle In cell biology, an organelle is a specialized subunit, usually within a cell (biology), cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as Organ (anatomy), organs are to the ...
membranes. Around the same time, the development of model membranes confirmed that the lipid bilayer is a stable structure that can exist independent of proteins. By “painting” a solution of lipid in organic solvent across an aperture, Mueller and Rudin were able to create an artificial bilayer and determine that this exhibited lateral fluidity, high electrical resistance and self-healing in response to puncture, all of which are properties of a natural cell membrane. A few years later, Alec Bangham showed that bilayers, in the form of lipid vesicles, could also be formed simply by exposing a dried lipid sample to water. This was an important advance, since it demonstrated that lipid bilayers form spontaneously via self assembly and do not require a patterned support structure. In 1977, a totally synthetic bilayer membrane was prepared by Kunitake and Okahata, from a single organic compound, didodecyldimethylammonium bromide. It clearly shows that the bilayer membrane was assembled by the
van der Waals interaction In molecular physics, the van der Waals force is a distance-dependent interaction between atoms or molecules. Unlike ionic bond, ionic or covalent bonds, these attractions do not result from a Chemical bond, chemical electronic bond; they are c ...
.

*
Surfactant Surfactants are chemical compounds that decrease the surface tension between two liquids, between a gas and a liquid, or interfacial tension between a liquid and a solid. Surfactants may act as detergents, wetting agents, emulsion#Emulsifiers , ...
* Membrane biophysics * Lipid polymorphism * Lipidomics

# References

Avanti Lipids
One of the largest commercial suppliers of lipids. Technical information on lipid properties and handling and lipid bilayer preparation techniques.

An extensive database of lipid physical properties

Simulations and publication links related to the cross sectional structure of lipid bilayers.

(requires Java plugin) Pictures and movies showing the results of molecular dynamics simulations of lipid bilayers.

from the Stephen White laboratory at
University of California, Irvine The University of California, Irvine (UCI or UC Irvine) is a Public university, public Land-grant university, land-grant research university in Irvine, California. One of the ten campuses of the University of California system, UCI offers 87 und ...

Animations of lipid bilayer dynamics
(requires Flash plugin) {{DEFAULTSORT:Lipid Bilayer Biological matter Membrane biology