Editing Lipid bilayer (section)

== Structure and organization ==

When phospholipids are exposed to water, they [[Molecular self-assembly|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]]s or salts that dissolve in water. The assembly process and maintenance are driven by aggregation of hydrophobic molecules (also called the [[hydrophobic effect]]). This complex process includes [[non-covalent interactions]] such as [[van der Waals force]]s, [[electrostatic]] and [[hydrogen bonds]].<ref name="Chen 2010">{{cite journal |first1=Irene A. |last1=Chen |first2= Peter |last2=Walde |title=From Self-Assembled Vesicles to Protocells |journal=[[Cold Spring Harbor Perspectives in Biology]] |date=July 2010 |volume=2 |issue=7 |page=a002170 |doi= 10.1101/cshperspect.a002170 |pmc=2890201 |pmid=20519344}}</ref>

=== Cross-section analysis ===

[[File:Bilayer hydration profile.svg|right|thumb|310px |Schematic cross sectional profile of a typical lipid bilayer. There are three distinct regions: the fully hydrated headgroups, the fully dehydrated alkane core and a short intermediate region with partial hydration. Although the head groups are neutral, they have significant dipole moments that influence the molecular arrangement.<ref>Mashaghi et al. Hydration strongly affects the molecular and electronic structure of membrane phospholipids. 136, 114709 (2012){{cite web |url=http://jcp.aip.org/resource/1/jcpsa6/v136/i11/p114709_s1 |title=The Journal of Chemical Physics |access-date=2012-05-17 |url-status=dead |archive-url=http://arquivo.pt/wayback/20160515021109/http://jcp.aip.org/resource/1/jcpsa6/v136/i11/p114709_s1 |archive-date=15 May 2016 |df=dmy-all }}</ref>]]

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&nbsp;ft/30&nbsp;cm), the lipid bilayer making up the [[plasma membrane]] 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]],<ref name=Lewis1983>{{cite journal |vauthors=Lewis BA, Engelman DM |title=Lipid bilayer thickness varies linearly with acyl chain length in fluid phosphatidylcholine vesicles |journal=Journal of Molecular Biology |volume=166 |issue=2 |pages=211–7 |date=May 1983 |pmid=6854644 |doi=10.1016/S0022-2836(83)80007-2 }}</ref> [[neutron scattering]],<ref name=Zaccai1975>{{cite journal |vauthors=Zaccai G, Blasie JK, Schoenborn BP |title=Neutron Diffraction Studies on the Location of Water in Lecithin Bilayer Model Membranes |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=72 |issue=1 |pages=376–380 |date=January 1975 |pmid=16592215 |pmc=432308 |doi=10.1073/pnas.72.1.376 |bibcode=1975PNAS...72..376Z |doi-access=free }}</ref> and [[nuclear magnetic resonance]] techniques.<ref name="Skarjune 1982">{{cite journal |last=Skarjune |first=Robert |last2=Oldfield |first2=Eric |title=Physical studies of cell surface and cell membrane structure. Deuterium nuclear magnetic resonance studies of N-palmitoylglucosylceramide (cerebroside) head group structure |journal=Biochemistry |volume=21 |issue=13 |date=22 June 1982 |issn=0006-2960 |doi=10.1021/bi00256a019 |pages=3154–3160}}</ref>

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&nbsp;nm thick. In [[phospholipid]] bilayers the [[phosphate]] group is located within this hydrated region, approximately 0.5&nbsp;nm outside the hydrophobic core.<ref name=Nagle2000>{{cite journal |vauthors=Nagle JF, Tristram-Nagle S |title=Structure of lipid bilayers |journal=Biochim. Biophys. Acta |volume=1469 |issue=3 |pages=159–95 |date=November 2000 |pmid=11063882 |pmc=2747654 |doi=10.1016/S0304-4157(00)00016-2}}</ref> 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]] coat on a bacterial outer membrane.<ref name="Avila-Calderón_2021">{{cite journal |vauthors=Avila-Calderón ED, Ruiz-Palma MD, Aguilera-Arreola MG, Velázquez-Guadarrama N, Ruiz EA, Gomez-Lunar Z, Witonsky S, Contreras-Rodríguez A |display-authors=6 |title=Outer Membrane Vesicles of Gram-Negative Bacteria: An Outlook on Biogenesis |journal=Frontiers in Microbiology |volume=12 |pages=557902 |year=2021 |pmid=33746909 |pmc=7969528 |doi=10.3389/fmicb.2021.557902 |doi-access=free }}</ref>

[[File:Bacillus subtilis.jpg|thumb|240px |[[Transmission electron microscopy|TEM]] image of a bacterium. The furry appearance on the outside is due to a coat of long-chain sugars attached to the cell membrane. This coating helps trap water to prevent the bacterium from becoming dehydrated.]]

Next to the hydrated region is an intermediate region that is only partially hydrated. This boundary layer is approximately 0.3&nbsp;nm thick. Within this short distance, the water concentration drops from 2M on the headgroup side to nearly zero on the tail (core) side.<ref name=Marsh2001>{{cite journal |author=Marsh D |title=Polarity and permeation profiles in lipid membranes |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=98 |issue=14 |pages=7777–82 |date=July 2001 |pmid=11438731 |pmc=35418 |doi=10.1073/pnas.131023798 |bibcode=2001PNAS...98.7777M |doi-access=free }}</ref><ref name=Marsh2002>{{cite journal |author=Marsh D |title=Membrane water-penetration profiles from spin labels |journal=Eur. Biophys. J. |volume=31 |issue=7 |pages=559–62 |date=December 2002 |pmid=12602343 |doi=10.1007/s00249-002-0245-z |s2cid=36212541 }}</ref> The hydrophobic core of the bilayer is typically 3-4&nbsp;nm thick, but this value varies with chain length and chemistry.<ref name=Lewis1983/><ref name=Rawicz2000>{{cite journal |vauthors=Rawicz W, Olbrich KC, McIntosh T, Needham D, Evans E |title=Effect of chain length and unsaturation on elasticity of lipid bilayers |journal=Biophys. J. |volume=79 |issue=1 |pages=328–39 |date=July 2000 |pmid=10866959 |pmc=1300937 |doi=10.1016/S0006-3495(00)76295-3 |bibcode=2000BpJ....79..328R}}</ref> Core thickness also varies significantly with temperature, in particular near a phase transition.<ref name=Trauble1971>{{cite journal |vauthors=Trauble H, Haynes DH |title=The volume change in lipid bilayer lamellae at the crystalline-liquid crystalline phase transition |journal=Chem. Phys. Lipids |volume=7 |issue=4 |pages=324–35 |year=1971 |doi=10.1016/0009-3084(71)90010-7}}</ref>

===Asymmetry===
In many naturally occurring bilayers, the compositions of the inner and outer membrane leaflets are different. In human [[erythrocyte|red blood cells]], the inner (cytoplasmic) leaflet is composed mostly of [[phosphatidylethanolamine]], [[phosphatidylserine]] and [[phosphatidylinositol]] and its phosphorylated derivatives. By contrast, the outer (extracellular) leaflet is based on [[phosphatidylcholine]], [[sphingomyelin]] and a variety of glycolipids.<ref name=Bretscher1972>{{cite journal|title=Asymmetrical Lipid Bilayer Structure for Biological Membranes|journal=Nature New Biology|date=1 March 1972|volume=236|issue=61|pages=11–12|doi=10.1038/newbio236011a0|pmid=4502419 |author=Bretscher MS }}</ref><ref name=Verkleij1973>{{cite journal |vauthors=Verkleij AJ, Zwaal RF, Roelofsen B, Comfurius P, Kastelijn D, van Deenen LL |title=The asymmetric distribution of phospholipids in the human red cell membrane. A combined study using phospholipases and freeze-etch electron microscopy |journal=Biochim. Biophys. Acta |volume=323 |issue=2 |pages=178–93 |date=October 1973 |pmid=4356540 |doi=10.1016/0005-2736(73)90143-0}}</ref><ref>{{Cite journal|last1=Coones|first1=R. T.|last2=Green|first2=R. J.|last3=Frazier|first3=R. A.|date=2021|title=Investigating lipid headgroup composition within epithelial membranes: a systematic review|url=http://xlink.rsc.org/?DOI=D1SM00703C|journal=Soft Matter|language=en|volume=17|issue=28|pages=6773–6786|doi=10.1039/D1SM00703C|pmid=34212942|bibcode=2021SMat...17.6773C|s2cid=235708094|issn=1744-683X|doi-access=free}}</ref> In some cases, this asymmetry is based on where the lipids are made in the cell and reflects their initial orientation.<ref name=Bell1981>{{cite journal |vauthors=Bell RM, Ballas LM, Coleman RA |title=Lipid topogenesis |journal=J. Lipid Res. |volume=22 |issue=3 |pages=391–403 |date=1 March 1981|doi=10.1016/S0022-2275(20)34952-X |pmid=7017050 |url=http://www.jlr.org/cgi/pmidlookup?view=long&pmid=7017050 |doi-access=free }}</ref> 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]], the phosphatidylserine&nbsp;— normally localised to the cytoplasmic leaflet&nbsp;— is transferred to the outer surface: There, it is recognised by a [[macrophage]] that then actively scavenges the dying cell.<ref name=Fadoka1998/>

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]]s.<ref name=Bretscher1973>{{cite journal |doi=10.1126/science.181.4100.622 |author=Bretscher MS |title=Membrane structure: some general principles |journal=Science |volume=181 |issue=4100 |pages=622–629 |date=August 1973 |pmid=4724478 |bibcode=1973Sci...181..622B |s2cid=34501546 }}</ref><ref name=Rothman1977>{{cite journal |vauthors=Rothman JE, Kennedy EP |title=Rapid transmembrane movement of newly synthesized phospholipids during membrane assembly |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=74 |issue=5 |pages=1821–5 |date=May 1977 |pmid=405668 |pmc=431015 |doi=10.1073/pnas.74.5.1821 |bibcode=1977PNAS...74.1821R |doi-access=free }}</ref> 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.<ref name=Kornberg1971>{{cite journal |vauthors=Kornberg RD, McConnell HM |title=Inside-outside transitions of phospholipids in vesicle membranes |journal=Biochemistry |volume=10 |issue=7 |pages=1111–20 |date=March 1971 |pmid=4324203 |doi=10.1021/bi00783a003 }}</ref>

It is possible to mimic this asymmetry in the laboratory in model bilayer systems. Certain types of very small artificial [[Vesicle (biology)|vesicle]] will automatically make themselves slightly asymmetric, although the mechanism by which this asymmetry is generated is very different from that in cells.<ref name=Litman1974>{{cite journal |author=Litman BJ |title=Determination of molecular asymmetry in the phosphatidylethanolamine surface distribution in mixed phospholipid vesicles |journal=Biochemistry |volume=13 |issue=14 |pages=2844–8 |date=July 1974 |pmid=4407872 |doi=10.1021/bi00711a010 }}</ref> By utilizing two different monolayers in [[Langmuir-Blodgett film|Langmuir-Blodgett]] deposition<ref name=Crane2005>{{cite journal |vauthors=Crane JM, Kiessling V, Tamm LK |title=Measuring lipid asymmetry in planar supported bilayers by fluorescence interference contrast microscopy |journal=Langmuir |volume=21 |issue=4 |pages=1377–88 |date=February 2005 |pmid=15697284 |doi=10.1021/la047654w }}</ref> or a combination of Langmuir-Blodgett and vesicle rupture deposition<ref name=Kalb1992>{{cite journal |vauthors=Kalb E, Frey S, Tamm LK |title=Formation of supported planar bilayers by fusion of vesicles to supported phospholipid monolayers |journal=Biochim. Biophys. Acta |volume=1103 |issue=2 |pages=307–16 |date=January 1992 |pmid=1311950 |doi=10.1016/0005-2736(92)90101-Q}}</ref> 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.<ref name=Lin2006>{{cite journal |vauthors=Lin WC, Blanchette CD, Ratto TV, Longo ML |title=Lipid asymmetry in DLPC/DSPC-supported lipid bilayers: a combined AFM and fluorescence microscopy study |journal=Biophys. J. |volume=90 |issue=1 |pages=228–37 |date=January 2006 |pmid=16214871 |pmc=1367021 |doi=10.1529/biophysj.105.067066 |bibcode=2006BpJ....90..228L }}</ref> However, it has been reported that lipid flip-flop is slow compare to cholesterol and other smaller molecules.<ref>{{Cite journal |last1=Perez-Salas |first1=Ursula |last2=Porcar |first2=Lionel |last3=Garg |first3=Sumit |last4=Ayee |first4=Manuela A. A. |last5=Levitan |first5=Irena |date=October 2022 |title=Effective Parameters Controlling Sterol Transfer: A Time-Resolved Small-Angle Neutron Scattering Study |url=https://pubmed.ncbi.nlm.nih.gov/35467109/ |journal=The Journal of Membrane Biology |volume=255 |issue=4–5 |pages=423–435 |doi=10.1007/s00232-022-00231-3 |issn=1432-1424 |pmid=35467109|s2cid=248375027 }}</ref><ref>{{Cite journal |last1=Garg |first1=S. |last2=Porcar |first2=L. |last3=Woodka |first3=A. C. |last4=Butler |first4=P. D. |last5=Perez-Salas |first5=U. |date=2011-07-20 |title=Noninvasive neutron scattering measurements reveal slower cholesterol transport in model lipid membranes |journal=Biophysical Journal |volume=101 |issue=2 |pages=370–377 |doi=10.1016/j.bpj.2011.06.014 |issn=1542-0086 |pmc=3136766 |pmid=21767489|bibcode=2011BpJ...101..370G }}</ref>

It has been reported that the organization and dynamics of the lipid monolayers in a bilayer are coupled.<ref name=":0">{{Cite journal |last1=Deverall |first1=Miranda A. |last2=Garg |first2=Sumit |last3=Lüdtke |first3=Karin |last4=Jordan |first4=Rainer |last5=Rühe |first5=Jürgen |last6=Naumann |first6=Christoph A. |date=2008-08-12 |title=Transbilayer coupling of obstructed lipid diffusion in polymer-tethered phospholipid bilayers |url=https://pubs.rsc.org/en/content/articlelanding/2008/sm/b800801a |journal=Soft Matter |language=en |volume=4 |issue=9 |pages=1899–1908 |doi=10.1039/B800801A |bibcode=2008SMat....4.1899D |issn=1744-6848}}</ref><ref name=":1">{{Cite journal |last1=Garg |first1=Sumit |last2=Rühe |first2=Jürgen |last3=Lüdtke |first3=Karin |last4=Jordan |first4=Rainer |last5=Naumann |first5=Christoph A. |date=2007-02-15 |title=Domain Registration in Raft-Mimicking Lipid Mixtures Studied Using Polymer-Tethered Lipid Bilayers |journal=Biophysical Journal |language=en |volume=92 |issue=4 |pages=1263–1270 |doi=10.1529/biophysj.106.091082 |pmid=17114215 |pmc=1783876 |bibcode=2007BpJ....92.1263G |issn=0006-3495}}</ref> For example, introduction of obstructions in one monolayer can slow down the lateral diffusion in both monolayers.<ref name=":0" /> 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.<ref name=":1" />

=== Phases and phase transitions ===

{{further|Lipid bilayer phase behavior}}

[[File:Lipid unsaturation effect.svg|right|thumb|350px|Diagram showing the effect of unsaturated lipids on a bilayer. The lipids with an unsaturated tail (blue) disrupt the packing of those with only saturated tails (black). The resulting bilayer has more free space and is, as a consequence, more permeable to water and other small molecules.]]

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]] exchange allows lipid to [[diffusion|diffuse]] and thus wander across the surface of the membrane.Unlike liquid phase bilayers, the lipids in a gel phase bilayer have less mobility.<ref name=Berg1993>{{cite book |author=Berg, Howard C. |title=Random walks in biology |publisher=Princeton University Press |location=Princeton, N.J |year=1993 |isbn=978-0-691-00064-0 |edition=Extended Paperback}}</ref> 

The phase behavior of lipid bilayers is determined largely by the strength of the attractive [[van der Waals force|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.<ref name=Rawicz2000/> Transition temperature can also be affected by the [[degree of unsaturation]] of the lipid tails. An unsaturated [[double bond]] can produce a kink in the [[alkane]] chain, disrupting the lipid packing. This disruption creates extra free space within the bilayer that allows additional flexibility in the adjacent chains.<ref name=Rawicz2000/> 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.<ref>{{cite web |title=Fats and oils |url=https://www.heartuk.org.uk/low-cholesterol-foods/fats-and-oils |website=Heart UK: The Cholesterol Charity |access-date=1 December 2024}}</ref>

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.<ref name=Dietrich2001>{{cite journal |vauthors=Dietrich C, Volovyk ZN, Levi M, Thompson NL, Jacobson K |title=Partitioning of Thy-1, GM1, and cross-linked phospholipid analogs into lipid rafts reconstituted in supported model membrane monolayers |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=98 |issue=19 |pages=10642–7 |date=September 2001 |pmid=11535814 |pmc=58519 |doi=10.1073/pnas.191168698 |bibcode=2001PNAS...9810642D |doi-access=free }}</ref> One particularly important component of many mixed phase systems is [[cholesterol]], which modulates bilayer permeability, mechanical strength, and biochemical interactions.<ref name="isbn1-4292-4646-4">{{cite book |vauthors=Sadava D, Hillis DM, Heller HC, Berenbaum MR |chapter=Cell Membranes |title=Life: The Science of Biology |edition=9th |publisher=Freeman |location=San Francisco |year=2011 |pages=105–114 |isbn=978-1-4292-4646-0 }}</ref>

===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]]s, but [[sphingolipids]] and [[sterol]]s such as [[cholesterol]] are also important components.<ref>{{cite book|last1=Alberts |first1=Bruce |title=Molecular Biology of the Cell |date=2017 |publisher=Garland Science |isbn=9781317563747 |chapter-url=https://books.google.com/books?id=2xIwDwAAQBAJ |chapter=Chapter 10: Membrane Structures}}</ref> Of the phospholipids, the most common headgroup is [[phosphatidylcholine]] (PC), accounting for about half the phospholipids in most mammalian cells.<ref name=Yeagle1993/> PC is a [[zwitterion]]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.<ref name="Ko 2015">{{cite journal |last=Ko |first=Du Young |last2=Patel |first2=Madhumita |last3=Jung |first3=Bo Kyoeng |last4=Park |first4=Jin Hye |last5=Jeong |first5=Byeongmoon |title=Phosphorylcholine-Based Zwitterionic Biocompatible Thermogel |journal=Biomacromolecules |volume=16 |issue=12 |date=14 December 2015 |doi=10.1021/acs.biomac.5b01169 |pages=3853–3862}}</ref>

Other headgroups are also present to varying degrees and can include [[phosphatidylserine]] (PS) [[phosphatidylethanolamine]] (PE) and [[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]]s is a marker of cell [[apoptosis]],<ref name=Fadoka1998>{{cite journal |vauthors=Fadok VA, Bratton DL, Frasch SC, Warner ML, Henson PM |title=The role of phosphatidylserine in recognition of apoptotic cells by phagocytes |journal=Cell Death Differ. |volume=5 |issue=7 |pages=551–62 |date=July 1998 |pmid=10200509 |doi=10.1038/sj.cdd.4400404 |doi-access=free }}</ref> whereas PS in [[growth plate]] vesicles is necessary for the [[nucleation]] of [[hydroxyapatite]] crystals and subsequent bone mineralization.<ref name=Anderson2005>{{cite journal |vauthors=Anderson HC, Garimella R, Tague SE |title=The role of matrix vesicles in growth plate development and biomineralization |journal=Frontiers in Bioscience |volume=10 |issue= 1–3|pages=822–37 |date=January 2005 |pmid=15569622 |url=http://www.bioscience.org/2005/v10/af/1576/fulltext.htm |doi=10.2741/1576}}</ref><ref name=Eanes1987>{{cite journal |vauthors=Eanes ED, Hailer AW |title=Calcium phosphate precipitation in aqueous suspensions of phosphatidylserine-containing anionic liposomes |journal=Calcif. Tissue Int. |volume=40 |issue=1 |pages=43–8 |date=January 1987 |pmid=3103899 |doi=10.1007/BF02555727 |s2cid=26435152 }}</ref> Unlike PC, some of the other headgroups carry a net charge, which can alter the electrostatic interactions of small molecules with the bilayer.<ref name=Kim1991>{{cite journal |vauthors=Kim J, Mosior M, Chung LA, Wu H, McLaughlin S |title=Binding of peptides with basic residues to membranes containing acidic phospholipids |journal=Biophysics Journal |volume=60 |issue=1 |pages=135–48 |date=July 1991 |pmid=1883932 |pmc=1260045 |doi=10.1016/S0006-3495(91)82037-9 |bibcode=1991BpJ....60..135K}}</ref>