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The lipid bilayer (or phospholipid bilayer) is a thin
polar membrane A polarized membrane is a lipid bilayer, lipid membrane that has a positive electrical charge on one side and a negative charge on another side, which produces the resting potential in living cells. Whether or not a membrane is polarized is determi ...
made of two layers of
lipid In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechanisms ...
molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an electrically neutral group of two or more atoms held together by chemical bo ...

molecule
s. These membranes are flat sheets that form a continuous barrier around all
cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a small room, hut, or cave in which a monk or religious recluse lives * Prison cell, a room used to hold peopl ...
. The
cell membrane cell membrane vs. Prokaryotes 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 the interior of all cells from the out ...
s of almost all
organisms In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mecha ...

organisms
and many
virus A virus is a submicroscopic infectious agent that Viral replication, replicates only inside the living Cell (biology), cells of an organism. Viruses infect all types of life forms, from animals and plants to microorganisms, including bacte ...

virus
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 The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a c ...

nuclear membrane
surrounding the
cell nucleus In cell biology, the nucleus (pl. ''nuclei''; from Latin or , meaning ''kernel'' or ''seed'') is a biological membrane#Function, membrane-bound organelle found in eukaryote, eukaryotic cell (biology), cells. Eukaryotes usually have a single nu ...

cell nucleus
, and
membranes Image:Schematic size.jpg, up150px, Schematic of size-based membrane exclusion A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Biological membr ...
of the membrane-bound organelles in the cell. The lipid bilayer is the barrier that keeps
ion An ion () is a particle In the Outline of physical science, physical sciences, a particle (or corpuscule in older texts) is a small wikt:local, localized physical body, object to which can be ascribed several physical property, physical or ...
s,
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 metabol ...

protein
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 The nanometre (international spelling as used by the International Bureau of Weights and Measures; SI symbol: nm) or nanometer (American and British English spelling differences#-re, -er, American spelling) is a units of measurement, unit of leng ...
s in width, because they are impermeable to most water-soluble (
hydrophilic A hydrophile is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an electrically neutral group of two or more atoms ...
) molecules. Bilayers are particularly impermeable to ions, which allows cells to regulate salt concentrations and
pH
pH
by transporting ions across their membranes using proteins called ion pumps. Biological bilayers are usually composed of
amphiphilic 250px, Cross-section view of the structures that can be formed by phospholipids, biological amphiphiles in aqueous solutions. Unlike this illustration, micelles are usually formed by non-biological, single-chain, amphiphiles, soaps or detergents, ...
phospholipid Phospholipids, also known as phosphatides, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group, and two hydrophobic "tails" derived from fatty acids, joined by a glycerol molecule. The phosphate group ca ...

phospholipid
s that have a hydrophilic phosphate head and a
hydrophobic In chemistry Chemistry is the scientific discipline involved with Chemical element, elements and chemical compound, compounds composed of atoms, molecules and ions: their composition, structure, properties, behavior and the changes they ...
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 Phase or phases may refer to: Science * State of matter, or phase, one of the distinct forms in which matter can exist *Phase (matter) In the physical sciences, a phase is a region of space (a thermodynamic system A thermodynamic system is a ...
of the bilayer. The bilayer can adopt a solid
gel A gel is a semi-solid that can have properties ranging from soft and weak to hard and tough. Gels are defined as a substantially dilute cross-linked system, which exhibits no flow when in the steady-state. A gel has been defined phenomenologica ...

gel
phase state at lower temperatures but undergo
phase transition In chemistry, thermodynamics, and many other related fields, phase transitions (or phase changes) are the Physical process, physical processes of transition between a state of a medium, identified by some parameters, and another one, with differe ...
to a
fluid state
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 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 of ...
made by model bilayers have also been used clinically to deliver drugs
Biological membrane A biological membrane, biomembrane or cell membrane is a selectively permeable membrane that separates cell from the external environment or creates intracellular compartments. Biological membranes, in the form of eukaryotic Eukaryotes ...
s typically include several types of molecules other than phospholipids. A particularly important example in animal cells is
cholesterol Cholesterol is any of a class of certain organic compound, organic molecules. A cholesterol is a sterol (or chemical modification, modified steroid), a type of lipid. Cholesterol is biosynthesis, biosynthesized by all animal Cell (biology)#Euka ...

cholesterol
, which helps strengthen the bilayer and decrease its permeability. Cholesterol also helps regulate the activity of certain
integral membrane protein An integral membrane protein (IMP) is a type of membrane protein Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Int ...
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 shellAnnular lipids (also called shell lipids or boundary lipids) are a set of lipid In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, ...
. 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 Fertilisation or fertilization (see spelling differences), also known as generative fertilisation, syngamy and impregnation, is the fusion of gametes to give rise to a new individual organism or offspring and initiate ...
during
fertilization Fertilisation or fertilization (see spelling differences), also known as generative fertilisation, syngamy and impregnation, is the fusion of gametes to give rise to a new individual organism or offspring and initiate its development. Proc ...

fertilization
of an
egg Diagram of a chicken egg in its 9th day. Membranes: allantois, chorion, amnion, and vitellus/ yolk. An egg is the organic vessel containing the zygote in which an embryo develops until it can survive on its own, at which point the animal ha ...
by a
sperm Sperm is the male Male (♂) is the sex of an organism that produces the gamete known as sperm. A male gamete can fuse with a larger female gamete, or ovum, in the process of fertilization. A male cannot sexual reproduction, reproduce sexuall ...

sperm
, or the entry of a
virus A virus is a submicroscopic infectious agent that Viral replication, replicates only inside the living Cell (biology), cells of an organism. Viruses infect all types of life forms, from animals and plants to microorganisms, including bacte ...

virus
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 high ...
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 The nanometre (international spelling as u ...
.


Structure and organization

When phospholipids are exposed to water, they
self-assemble
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. Table sugar, granulated sugar, or regular sugar, refers to sucrose, a disaccharide composed of glucose and fructose. Simple sugars, ...

sugar
s or salts that dissolve in water. The assembly process is driven by interactions between hydrophobic molecules (also called the
hydrophobic effect thumbnail, 250px, A droplet of water forms a spherical shape, minimizing contact with the hydrophobic leaf. The hydrophobic effect is the observed tendency of nonpolar substances to aggregate in an aqueous solution An aqueous solution is a sol ...
). 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 interactionsA 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 chemical energy re ...
such as
van der Waals force In molecular physics, the Van der Waals force, named after Dutch physicist Johannes Diderik van der Waals, is a distance-dependent interaction between atoms or molecules. Unlike ionic bond, ionic or covalent bonds, these attractions do not result ...
s,
electrostatic Electrostatics is a branch of physics Physics is the natural science that studies matter, its Elementary particle, fundamental constituents, its Motion (physics), motion and behavior through Spacetime, space and time, and the related enti ...
and
hydrogen bonds A hydrogen bond (or H-bond) is a primarily Electrostatics, electrostatic force of attraction between a hydrogen Hydrogen is the chemical element Image:Simple Periodic Table Chart-blocks.svg, 400px, Periodic table, The periodic table of ...
.


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 cell membrane vs. Prokaryotes A prokaryote () is a single-celled organism A unicellular organism, also known as a single-celled organism, is an organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''organ ...
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,
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. The ...
and
nuclear magnetic resonance Nuclear magnetic resonance (NMR) is a physical phenomenon in which 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 an electromagne ...
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, also known as phosphatides, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group, and two hydrophobic "tails" derived from fatty acids, joined by a glycerol molecule. The phosphate group ca ...

phospholipid
bilayers the
phosphate In chemistry Chemistry is the scientific discipline involved with Chemical element, elements and chemical compound, compounds composed of atoms, molecules and ions: their composition, structure, properties, behavior and the changes they un ...

phosphate
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), also known as endotoxins, are large molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an e ...

lipopolysaccharide
coat on a bacterial outer membrane, which helps retain a water layer around the
bacterium Bacteria (; common noun bacteria, singular bacterium) are a type of biological cell The cell (from Latin ''cella'', meaning "small room") is the basic structural, functional, and biological unit of all known organisms. Cells are the sma ...
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 ''erythros'' for "red" and ''kytos'' for "holl ...

red blood cells
, the inner (cytoplasmic) leaflet is composed mostly of
phosphatidylethanolamine Phosphatidylethanolamine (PE) is a class of phospholipid Phospholipids, also known as phosphatides, are a class of lipid In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical ...

phosphatidylethanolamine
,
phosphatidylserine Phosphatidylserine (abbreviated Ptd-L-Ser or PS) is a phospholipid and is a component of the cell membrane. It plays a key role in cell cycle signaling, specifically in relation to apoptosis. It is a key pathway for viruses to enter cells via apo ...

phosphatidylserine
and
phosphatidylinositol Phosphatidylinositol 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 phosphatidylglycerides. In such molecules the isomer of the inosit ...

phosphatidylinositol
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 soybeans, ...

phosphatidylcholine
,
sphingomyelin Sphingomyelin (SPH, ˌsfɪŋɡoˈmaɪəlɪn) is a type of sphingolipid Sphingolipids are a class of lipid In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Bioch ...

sphingomyelin
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 Ancient Greek Ancient Greek includes the forms of the Greek language used in ancient Greece and the classical antiquity, ancient world from around 1500 BC to 300 BC. It is often roughly divided into the following periods: ...

apoptosis
, the phosphatidylserine — normally localised to the cytoplasmic leaflet — is transferred to the outer surface: There, it is recognised by a
macrophage Macrophages (abbreviated as M 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 anything that does not have o ...

macrophage
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
flippase Flippases (rarely spelled flipases) are transmembrane lipid transporter protein Proteins are large biomolecules or macromolecules that are comprised of one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a va ...

flippase
s. 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) s in an aqueous An aqueous solution is a solution Image:SaltInWaterSolutionLiquid.jpg, Making a saline water solution by dissolving Salt, table salt ...
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.


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 Mathematics (from Ancient Greek, Greek: ) includes the study of such topics as quantity (number theory), mathematical structure, structure (algebra), space (geometry), and calculus, change (mathematical analysis, analysis) ...
exchange allows lipid to
diffuse 250px, Diffusion from a microscopic and macroscopic point of view. Initially, there are solution, solute molecules on the left side of a barrier (purple line) and none on the right. The barrier is removed, and the solute diffuses to fill the wh ...

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 ...

double bond
can produce a kink in the
alkane , the simplest alkane In organic chemistry, an alkane, or paraffin (a historical trivial name that also has other meanings), is an acyclic Acyclic may refer to: * In chemistry, a compound which is an open-chain compound, e.g. alkanes and acyclic ...
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. A cholesterol is a sterol (or chemical modification, modified steroid), a type of lipid. Cholesterol is biosynthesis, biosynthesized by all animal Cell (biology)#Euka ...

cholesterol
, 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, also known as phosphatides, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group, and two hydrophobic "tails" derived from fatty acids, joined by a glycerol molecule. The phosphate group ca ...

phospholipid
s, but
sphingolipids Sphingolipids are a class of lipids containing a backbone of sphingoid bases, a set of aliphatic amino alcohols that includes sphingosine. They were discovered in brain extracts in the 1870s and were named after the mythological sphinx because ...
and
sterol Sterol is a chemical compound A chemical compound is a chemical substance composed of many identical molecules (or molecular entity, molecular entities) composed of atoms from more than one chemical element, element held together by chemical bon ...

sterol
s such as
cholesterol Cholesterol is any of a class of certain organic compound, organic molecules. A cholesterol is a sterol (or chemical modification, modified steroid), a type of lipid. Cholesterol is biosynthesis, biosynthesized by all animal Cell (biology)#Euka ...

cholesterol
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 soybeans, ...

phosphatidylcholine
(PC), accounting for about half the phospholipids in most mammalian cells. PC is a
zwitterionIn chemistry Chemistry is the scientific discipline involved with Chemical element, elements and chemical compound, compounds composed of atoms, molecules and ions: their composition, structure, properties, behavior and the changes they undergo ...
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 and is a component of the cell membrane. It plays a key role in cell cycle signaling, specifically in relation to apoptosis. It is a key pathway for viruses to enter cells via apo ...

phosphatidylserine
(PS)
phosphatidylethanolamine Phosphatidylethanolamine (PE) is a class of phospholipid Phospholipids, also known as phosphatides, are a class of lipid In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical ...

phosphatidylethanolamine
(PE) and
phosphatidylglycerol General chemical structure of a phosphatidyl glycerol where R1 and R2 are fatty acid side chains Phosphatidylglycerol is a glycerophospholipid found in pulmonary surfactant and in the plasma membrane where it directly activates lipid-gated ion chann ...

phosphatidylglycerol
(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 ''erythros'' for "red" and ''kytos'' for "holl ...

erythrocyte
s is a marker of cell
apoptosis Apoptosis (from Ancient Greek Ancient Greek includes the forms of the Greek language used in ancient Greece and the classical antiquity, ancient world from around 1500 BC to 300 BC. It is often roughly divided into the following periods: ...

apoptosis
, whereas PS in
growth plate Growth may refer to:"''Quantative increase in size''". Biology * Auxology, the study of all aspects of human physical growth * Bacterial growth * Cell growth * Growth hormone, a peptide hormone that stimulates growth * Human development (biology) ...
vesicles is necessary for the
nucleation Nucleation is the first step in the formation of either a new thermodynamic phase or a new structure via self-assembly File:Iron oxide nanocube.jpg, upright=1.2, Transmission electron microscopy image of an iron oxide nanoparticle. Regularly arra ...

nucleation
of
hydroxyapatite Hydroxyapatite, also called hydroxylapatite (HA), is a naturally occurring mineral In geology and mineralogy, a mineral or mineral species is, broadly speaking, a solid chemical compound with a fairly well-defined chemical composition and a ...
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 Image:SaltInWaterSolutionLiquid.jpg, Making a saline water solution by dissolving Salt, table salt (sodium chloride, NaCl) in water. The salt is the solute and the water the solvent. In chemistry, a solution ...
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 ) constitute a domain Domain may refer to: Mathematics *Domain of a function, the set of input values for which the (total) function is defined **Domain of definition of a partial function **Natural domain of a pa ...

archaea
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
biosyntheticBiosynthesis 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 modi ...

biosynthetic
capability being the production of more
phospholipid Phospholipids, also known as phosphatides, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group, and two hydrophobic "tails" derived from fatty acids, joined by a glycerol molecule. The phosphate group ca ...

phospholipid
s. The partitioning ability of the lipid bilayer is based on the fact that
hydrophilic A hydrophile is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an electrically neutral group of two or more atoms ...
molecules cannot easily cross the
hydrophobic In chemistry Chemistry is the scientific discipline involved with Chemical element, elements and chemical compound, compounds composed of atoms, molecules and ions: their composition, structure, properties, behavior and the changes they ...
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 Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, M ...
.
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 cell membrane vs. Prokaryotes 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 the interior of all cells from the out ...
(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 cell membrane vs. Prokaryotes The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to a ...
, 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 metabol ...

protein
s or long chain
carbohydrate is a disaccharide found in animal milk. It consists of a molecule of D-galactose and a molecule of D-glucose bonded by beta-1-4 glycosidic linkage. A carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) ato ...
s, not lipids. In contrast,
eukaryote Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus enclosed within a nuclear envelope. Eukaryotes belong to the Domain (biology), domain Eukaryota or Eukarya; their name comes from the Greek language, Greek wi ...

eukaryote
s have a range of
organelle In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, M ...
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 ...

nucleus
,
mitochondria A mitochondrion (, plural mitochondria) is a double membrane-bound organelle found in most eukaryotic organisms. Some cells in some multicellular organisms lack mitochondria (for example, mature mammalian red blood cells). A number of unice ...

mitochondria
,
lysosome A lysosome () is a membrane-bound organelle found in many animal cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a small room, hut, or cave in which ...

lysosome
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 In cell biology Cell biology (also cellular biology or ...
. 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 carbohyd ...
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 transmissionImage:SynapseSchematic en.svg, 280px, The presynaptic neuron (top) releases a neurotransmitter, which activates receptors on the nearby postsynaptic cell (bottom). Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' ...
, whereby a nerve impulse that has reached the end of one
neuron A neuron or nerve cell is an membrane potential#Cell excitability, electrically excitable cell (biology), cell that communicates with other cells via specialized connections called synapses. It is the main component of nervous tissue in all Anima ...

neuron
is conveyed to an adjacent neuron via the release of
neurotransmitter A neurotransmitter is a signaling molecule In biology, cell signaling (cell signalling in British English), or cell-cell communication, governs the basic activities of cells and coordinates multiple-cell actions. A signal is an entity that ...
s. This transmission is made possible by the action of
synaptic vesicle In a neuron, synaptic vesicles (or neurotransmitter vesicles) store various neurotransmitters that are exocytosis, released at the chemical synapse, synapse. The release is regulated by a voltage-dependent calcium channel. Vesicle (biology), Vesic ...
s loaded with the neurotransmitters to be released. These vesicles
fuse Fuse or FUSE may refer to: Devices * Fuse (electrical), a device used in electrical systems to protect against excessive current ** Fuse (automotive), a class of fuses for vehicles * Fuse (hydraulic), a device used in hydraulic systems to protect ...

fuse
with the cell membrane at the pre-synaptic terminal and release its contents to the exterior of 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 membrane protein (IMP) is a type of membrane protein Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Int ...
s. This is an extremely broad and important class of biomolecule. It is estimated that up to a third of the human
proteome , transcriptome, proteome, and metabolome ( lipidome). The proteome is the entire set of proteins that is, or can be, expressed by a genome, cell, tissue, or organism at a certain time. It is the set of expressed proteins in a given type of cell ...
are membrane proteins. Some of these proteins are linked to the exterior of the cell membrane. An example of this is the CD59 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 ...

HIV
virus evades the
immune system The immune system is a network of biological processes that protects an organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''organismos'') is any individual contiguous system that embodies the Life#Biolog ...
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 evolutionarily-related prot ...
(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 and is a component of the cell membrane. It plays a key role in cell cycle signaling, specifically in relation to apoptosis. It is a key pathway for viruses to enter cells via apo ...

phosphatidylserine
-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 Endocytosis is a cellular process i ...

phagocytosis
. 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 Scramblase is a protein responsible for the translocation of phospholipids between the two monolayers of a lipid bilayer of a cell membrane. In humans, phospholipid scramblases (PLSCRs) constitute a family of five homologous proteins that ...
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 Resistance may refer to: Arts, entertainment, and media Comics * Either of two similarly named but otherwise unrelated comic book series, both published by Wildstorm: ** ''Resistance'' (comics), based on the video game of the same title ** ''Th ...
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 s (typically four per channel), 2 - outer vestibule, 3 - Potassium channel#Selectivity filter, selectivity filter, 4 - diameter of selectivity filter, 5 - phosphorylation site, 6 - cell membrane. Ion channels are pore-forming membrane proteins that ...

ion channel
s can be resolved.


Fluorescence microscopy

Electrical measurements do not provide an actual picture like imaging with a microscope can. Lipid bilayers cannot be seen in a traditional microscope because they are too thin. In order to see bilayers, 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 properties ...

fluorescence microscopy
. A sample is excited with one wavelength of light and observed in a different wavelength, so that only fluorescent molecules with a matching excitation and emission profile will be seen. Natural lipid bilayers are not fluorescent, so a dye is used that attaches to the desired molecules in the bilayer. Resolution is usually limited to a few hundred nanometers, much smaller than a typical cell but much larger than the thickness of a lipid bilayer.


Electron microscopy

Electron microscopy An electron microscope is a microscope A microscope (from grc, μικρός ''mikrós'' 'small' and ''skopeîn'' 'to look (at); examine, inspect') is a laboratory instrument used to examine objects that are too small to be seen by the na ...

Electron microscopy
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 high ...

electron microscope
, a beam of focused
electron The electron is a subatomic particle In physical sciences, subatomic particles are smaller than atom An atom is the smallest unit of ordinary matter In classical physics and general chemistry, matter is any substance that has ma ...

electron
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 In Biology, biology, the nervous system is a Complex system, highly complex part of an animal that coordinates its Behavior, actions and Sense, sensory information by transmitting action potential, signals to and from ...

synapse
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 The nanometre (international spelling as u ...
(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 optical Optics is the branch of physics Physics (from grc, φυσική (ἐπιστήμη), physikḗ (epistḗmē), knowledge of nature, from ''phýsis'' 'nature'), , is the natural science that studies matter, ...

birefringence
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 (also known as refraction index or index of refraction) of a optical medium, material is a dimensionless number that describes how fast EM radiation, light travels through the material. It is defined as :n = \frac, ...

refractive index
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 using the evanescent wave of a laser beam. It is used to measure the conformational change in proteins, or othe ...
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 singular of ''initium'' ("beginning"). Etymology , from Latin, , from ablative case of ''initium'' "entrance, begi ...
calculations of its properties is difficult and computationally expensive. Quantum chemical calculations has recently been successfully performed to estimate
dipole In electromagnetism Electromagnetism is a branch of physics involving the study of the electromagnetic force, a type of physical interaction that occurs between electric charge, electrically charged particles. The electromagnetic force is ca ...

dipole
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 ...

quadrupole
moments of lipid membranes.


Transport across the bilayer


Passive diffusion

Most
polar Polar may refer to: Geography Polar may refer to: * Geographical pole, either of two fixed points on the surface of a rotating body or planet, at 90 degrees from the equator, based on the axis around which a body rotates *Polar climate, the clim ...
molecules have low solubility in the
hydrocarbon In organic chemistry, a hydrocarbon is an organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, bonds. Due to carbon's a ...
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 An atom is the smallest unit of ordinary matter In classical physics and general chemistry, matter is any substance that has mass and takes up space by having volume. All everyday objects that can be touched are u ...
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 negative by convention and this charge is equal and opposite to charge of a proton, which is considered positive by convent ...
s. Compared to ions, water molecules actually have a relatively large permeability through the bilayer, as evidenced by . 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 with formula CH Cl3. It is a colorless, strong-smelling, dense liquid that is produced on a large scale as a precursor to PTFE Polytetrafluoroethylene (PTFE) is a synthetic fluoropoly ...

chloroform
and
ether Ethers are a class of organic compounds that contain an ether functional group, group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula R–O–R′, where R and R′ represent the alkyl or aryl groups. Ethers ...

ether
. 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 s (typically four per channel), 2 - outer vestibule, 3 - Potassium channel#Selectivity filter, selectivity filter, 4 - diameter of selectivity filter, 5 - phosphorylation site, 6 - cell membrane. Ion channels are pore-forming membrane proteins that ...

ion channel
s and ion pumps. Both pumps and channels are
integral membrane protein An integral membrane protein (IMP) is a type of membrane protein Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Int ...
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 Thermodynamics is a branch of physics that deals with heat, Work (thermodynamics), work, and temperature, and their relation to energy, radiation, and physical properties of matter. The behavior of these quantities is governed ...

chemical potential
. The energy source can be
ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals * American Technical Publishers * ', a Danish pension * Armenia Tree Project * Association for Transpersonal Psychology * ATP architects engineers office * ATP ...

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 via the . 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 In physiology, an action potential (AP) 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 i ...

action potential
along
neuron A neuron or nerve cell is an membrane potential#Cell excitability, electrically excitable cell (biology), cell that communicates with other cells via specialized connections called synapses. It is the main component of nervous tissue in all Anima ...

neuron
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 or budding of
vesicles 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 of ...
. 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 Image:Synapse diag1.svg, 300px, Exocytosis of neurotransmitters into a synapse from neuron A to neuron B. Exocytosis () is a form of active transport and solvent drag, bulk transport in which a cell transports molecules (e.g., neurotransmitters an ...
, popularly known as
membrane vesicle traffickingMembrane vesicle trafficking in ''eukaryotic'' animal cells involves movement of important biochemical signal molecules from synthesis-and-packaging locations in the Golgi body to specific 'release' locations on the inside of the plasma membrane ...
, a Nobel prize-winning (year, 2013) process, is traditionally regarded as a prerogative of
eukaryotic Eukaryotes () are organism In biology, an organism () is any organic, life, living system that functions as an individual entity. All organisms are composed of cells (cell theory). Organisms are classified by taxonomy (biology), tax ...
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 In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biol ...
, released by
gram-negative Gram-negative bacteria are bacteria Bacteria (; common noun bacteria, singular bacterium) are a type of Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typically a few microm ...
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 Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an electrically neutral gro ...

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 eukaryotic Eukaryotes () are organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''organismos'') is any indi ...

transfection
as well as bacterial
transformation Transformation may refer to: Science and mathematics In biology and medicine * Metamorphosis, the biological process of changing physical form after birth or hatching * Malignant transformation, the process of cells becoming cancerous * Transf ...
. It has even been proposed that electroporation resulting from
lightning Lightning is a naturally occurring electrostatic discharge Electrostatic discharge (ESD) is the sudden flow of electricity Electricity is the set of physical phenomena associated with the presence and motion Image:Leaving Yongsan S ...

lightning
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 A unicellular organism, also known as a single-celled organism, is an organism In biology, an organism (from Ancient G ...
. 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 showing the ribbon-like plasma filaments from a Tesla coil. Electrical breakdown or dielectric breakdown is a process that occurs when an Insulator (electricity), electrical insulating material, subjected to a high enough voltage Voltage, ...
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 The interdisciplinary field of materials science, also commonly termed materials science and engineering, covers the design and discovery of new materials, particularly solids. The intellectual origins of materials scienc ...
, 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 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 Image:Micelle scheme-en.svg, 250px, Scheme of a micelle formed by phospholipids in an aqueous solution A micelle () or micella () (plural micelles or micellae, respectively) is an aggregate (or supramolecular assembly) of surfactant phospholipid ...

micelle
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

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 enclosed within a nuclear envelope. Eukaryotes belong to the Domain (biology), domain Eukaryota or Eukarya; their name comes from the Greek language, Greek wi ...

eukaryote
s, since the eukaryotic cell is extensively sub-divided by lipid bilayer membranes.
Exocytosis Image:Synapse diag1.svg, 300px, Exocytosis of neurotransmitters into a synapse from neuron A to neuron B. Exocytosis () is a form of active transport and solvent drag, bulk transport in which a cell transports molecules (e.g., neurotransmitters an ...
,
fertilization Fertilisation or fertilization (see spelling differences), also known as generative fertilisation, syngamy and impregnation, is the fusion of gametes to give rise to a new individual organism or offspring and initiate its development. Proc ...

fertilization
of an
egg Diagram of a chicken egg in its 9th day. Membranes: allantois, chorion, amnion, and vitellus/ yolk. An egg is the organic vessel containing the zygote in which an embryo develops until it can survive on its own, at which point the animal ha ...
by , 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 submicroscopic infectious agent that Viral replication, replicates only inside the living Cell (biology), cells of an organism. Viruses infect all types of life forms, from animals and plants to microorganisms, including bacte ...

virus
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 protein, 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 submicroscopic infectious agent that Viral replication, replicates only inside the living Cell (biology), cells of an organism. Viruses infect all types of life forms, from animals and plants to microorganisms, including bacte ...

virus
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 cells also use fusion proteins, the best-studied of which are the SNARE (protein), SNAREs. SNARE proteins are used to direct all Vesicle (biology), 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 (PEG) causes fusion without significant aggregation or biochemical disruption. This procedure is now used extensively, for example by fusing B-cells with myeloma cells. The resulting “hybridoma” from this combination expresses a desired antibody as determined by the B-cell involved, but is immortalized due to the melanoma component. Fusion can also be artificially induced through electroporation in a process known as electrofusion. It is believed that this phenomenon results from the Lipid bilayer mechanics, 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, to define the boundaries of artificial cells. 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: * Model lipid bilayers#Black lipid membranes (BLM), Black lipid membranes (BLM) * Model lipid bilayers#Supported lipid bilayers (SLB), Supported lipid bilayers (SLB) * Model lipid bilayers#Tethered Bilayer Lipid Membranes (t-BLM), Tethered Bilayer Lipid Membranes (t-BLM) * Model lipid bilayers#Vesicles, Vesicles * Model lipid bilayer, Droplet Interface Bilayers (DIBs)


Commercial applications

To date, the most successful commercial application of lipid bilayers has been the use of liposomes 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) s in an aqueous An aqueous solution is a solution Image:SaltInWaterSolutionLiquid.jpg, Making a saline water solution by dissolving Salt, table salt ...
” 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 Metabolize, 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 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 Endocytosis is a cellular process i ...

phagocytosis
. Refinement of the lipid composition to tune fluidity, surface charge density, and surface hydration resulted in vesicles that adsorb fewer proteins from blood serum, serum and thus are less readily recognized by the
immune system The immune system is a network of biological processes that protects an organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''organismos'') is any individual contiguous system that embodies the Life#Biolog ...
. The most significant advance in this area was the grafting of polyethylene glycol (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 tissues. Because tumors induce rapid and uncontrolled angiogenesis 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 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 biosensors. 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 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 technique measures the permeability across specifically formulated lipid cocktail(s) found to be highly correlated with Caco-2 cultures, the gastrointestinal tract, blood–brain barrier 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 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 ''erythros'' for "red" and ''kytos'' for "holl ...

erythrocyte
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 high ...
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 Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, M ...
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 Douglas Bangham, 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.


See also

* Surfactant * Membrane biophysics * Lipid polymorphism * Lipidomics


References


External links


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