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It is commonly told that, hydrophobic/ lipophilic/ nonpolar molecules can quite easily pass phospholipid bilayer, and hydrophilic (polar or ionic) molecules can't pass (when no protein aid that); because hydrophobic nature of the lipid.
But in the same logic, hydrophobic molecules shouldn't pass through the bilayer. Because there are 2 hydrophilic layers in the membrane. i.e.
A and A' .
Then how the hydrophobic molecules can pass through A and A'?
I guess, it is due to thin diameter of A and A' . Is that?
Good question. This is my take.
It's not just the surface of the membrane that's polar. There is water (polar) on both sides of the membrane. In most animal cells there is also an unequal distribution of charges across the membrane. The environment outisde of the cell is typically positive due to an excess of positive ions, especially sodium. The inside of the cell is typically negative due to an excess of negative ions such as phosphate.
This means the hydrophobic molecules aren't any more at home in the environment outside, or inside, the membrane than they are at the surface. There's no reason to suppose any more repulsion at the surface. So, just due to their random kinetic motion they will find themselves at the membrane's surface, some with the necessary kinetic energy to cross.
There's another way to view this. We shouldn't think of the membrane as allowing hydrophobic substances to enter. We should think of it as NOT allowing hydrophyllic substance to enter without a proper ID check by proteins in the membrane.
Biology 1302 Exam 2
Phospholipids are not bound together - they only take their shape because of the clumping of the tails.
The resulting phospholipid bilayer functions to enclose the cell the hydrophilic & hydrophobic layers restrict movement, keeping the insides in & the outsides out
Remember: cholesterol is a hydrophobic lipid that animals make
wiggles in with the hydrophobic tails to make the cell membrane more stiff
The resulting phospholipid bilayer functions to enclose the cell
the hydrophilic & hydrophobic layers restrict movement, keeping the insides in & the outsides out
Because phospholipids are not bound together, the cell membrane is very flexible or "fluid"
The fatty acid tails of the phospholipids can alter how fluid or flexible the membrane is
Even though the phospholipid bilayer provides a barrier, some substances can still get across
Very small molecules like water & gases (CO2 & O2) can wiggle though the phospholipids
Can also pass: hydrophobic molecules - also called "lipophilic" molecules
Lipophilic molecules are lipid-loving, so they are able to move easily through the fatty acid layer
Even though some things can cross, the bilayer prevents many substances from crossing
Hydrophilic molecules can NOT cross the phospholipid bilayer
e.g. salts & sugars
Very large molecules also can NOT cross
However: we need to get salts, sugars, polysaccharides, & other large or hydrophilic molecules inside our cells in order to stay alive
PEGylation and its alternatives
14.2 PEGylated liposomes
Liposomes , microscopic and spherical manmade cells, are made from one or more lipid bilayers consisting of single amphiphilic lipids or different lipids either charged or neutral. These liposomes can entrap the therapeutic molecules such as drugs, vaccines, enzymes, proteins, oligonucleotides, genetic material and other biomolecules, and have been widely investigated as DDSs to enhance safety and effectiveness of the therapeutics  . Although liposomes are a safe and effective way to introduce therapeutic agents, they often suffer from opsonization, which removes liposomes circulating in blood stream and causes degradation of the liposomes. The physical properties and in vivo efficacy of the liposomes can be easily altered by modifying the few characteristics of lipids including chain length, unsaturation, composition, size, and zeta-potential [11,12] . The surface modification of the liposomes or camouflaging the liposomes with PEG—known as PEGylation of liposomes—gives modified liposomes known as PEGylated liposomes or stealth liposomes. In comparison with classical liposomes, these PEGylated liposomes have showed improved blood circulation capability, high bioavailability of the drugs by bypassing the digestive tract, minimal toxicity, and improved passive targeted drug delivery [12–14] . A number of stealth liposomes-based products are available on market and several of these versions are in advanced clinical trials. In particular, Doxil, AmBisome, and Visudyne have been widely used in clinical applications in different countries  .
Chapter 8 - Therapeutic Nanostructures for Dermal and Transdermal Drug Delivery
The term “nanoscale” describes particles as having a size varying from 1 to 100 nm, but in the pharmaceutical field, nanoparticles with the size of 50–500 nm are acceptable.
Transdermal drug delivery systems (TDDS) are controlled-release carriers for topical or systemic therapeutic effect after local application. Several methods have been studied for increasing the penetration into and through the skin of active pharmaceutical ingredients a nanoparticulate delivery system has potential use for this purpose. Recently, some nanoparticles for dermatological purposes including vesicular systems, such as liposomes along with other varieties of nanocarriers, such as nanoparticles, nanostructured lipid carriers, polymer-based nanoparticles, carbon nanotubes, and magnetic nanoparticles have been developed. Among skin nanocarriers that are developed, liposomes, transfersomes, ethosomes, niosomes, dendrimers, lipid and polymer nanoparticles, and nanoemulsions are the most used. In this chapter we are going to review these nanostructure systems in order to evaluate drug delivery to dermal and transdermal sites. Their fabrication, advantages, and disadvantages will also be discussed.
Pathway for membrane building blocks
With the corkscrew-shaped peptide binding a lipid molecule, the newly formed phospholipid can slip through the first membrane layer into the second. Credit: M. Langer, R. Sah, A. Veser, M. Gütlich, D. Langosch/Chemistry & Biology, Volume 20, 24 January 2013
Biomembranes consist of a mosaic of individual, densely packed lipid molecules. These molecules are formed inside the cells. But how do these building blocks move to the correct part of the membrane? Researchers from Technische Universität München have discovered a mechanism to show how this is done.
The lipid molecules of membranes, also known as phospholipids, are composed of two elements: A hydrophilic head and two long-chain fatty acids. The molecules form a bilayer in the membrane, with all of the heads pointing outwards and the fatty acid chains hanging in a zip-like interlay position.
Biomembranes are constantly reorganized or renewed, for example whenever cells divide. The cell is constantly creating new phospholipids that have to align themselves – which they do in both layers of the biomembrane. However, cells only produce phospholipids on one side of the biomembrane. From there, they need to be transported to the other half of the bilayer.
A helping hand through the membrane
The problem is that the hydrophilic and lipophilic parts of the molecule repel each other. "The molecules can anchor themselves in one of the two membrane layers with their lipophilic tail," explains Prof. Dieter Langosch of the TUM Chair of Biopolymer Chemistry. "Translocation to the second layer is not possible because the hydrophilic heads cannot pass through the lipophilic fatty acid chains."
The key to establishing order in the membranes lies in enzymes that transport the molecules to their correct location in the "second layer". Scientists have been searching for such enzymes – known as flippases – for many years. But now Prof. Langosch and his team have made a breakthrough. They experimented with synthetic peptides, which transport phospholipids through the membrane.
In this process, the researchers came across an indirect transport mechanism. The peptides span both layers of the membrane – and are able to bind to individual phospholipids. Prof. Langosch explains: "When the peptides bind the molecules, the surrounding membrane is briefly destabilized. The new phospholipids use this opportunity to slip through the barrier of the first lipid layer and flip to the second layer of the membrane."
The researchers now have a clear idea of how flippases work. "Our peptides stretch through the membrane like a corkscrew. If this "alpha-helix" has dynamic elements, it can bind to phospholipids," says Prof. Langosch. "This model will help us to detect the flippases."
Transport across Cell Membranes
The selective permeability of biological membranes to small molecules allows the cell to control and maintain its internal composition. Only small uncharged molecules can diffuse freely through phospholipid bilayers (Figure 2.49). Small nonpolar molecules, such as O2 and CO2, are soluble in the lipid bilayer and therefore can readily cross cell membranes. Small uncharged polar molecules, such as H2O, also can diffuse through membranes, but larger uncharged polar molecules, such as glucose, cannot. Charged molecules, such as ions, are unable to diffuse through a phospholipid bilayer regardless of size even H + ions cannot cross a lipid bilayer by free diffusion.
Permeability of phospholipid bilayers. Small uncharged molecules can diffuse freely through a phospholipid bilayer. However, the bilayer is impermeable to larger polar molecules (such as glucose and amino acids) and to ions.
Although ions and most polar molecules cannot diffuse across a lipid bilayer, many such molecules (such as glucose) are able to cross cell membranes. These molecules pass across membranes via the action of specific transmembrane proteins, which act as transporters. Such transport proteins determine the selective permeability of cell membranes and thus play a critical role in membrane function. They contain multiple membrane-spanning regions that form a passage through the lipid bilayer, allowing polar or charged molecules to cross the membrane through a protein pore without interacting with the hydrophobic fatty acid chains of the membrane phospholipids.
As discussed in detail in Chapter 12, there are two general classes of membrane transport proteins (Figure 2.50). Channel proteins form open pores through the membrane, allowing the free passage of any molecule of the appropriate size. Ion channels, for example, allow the passage of inorganic ions such as Na + , K + , Ca 2+ , and Cl - across the plasma membrane. Once open, channel proteins form small pores through which ions of the appropriate size and charge can cross the membrane by free diffusion. The pores formed by these channel proteins are not permanently open rather, they can be selectively opened and closed in response to extracellular signals, allowing the cell to control the movement of ions across the membrane. Such regulated ion channels have been particularly well studied in nerve and muscle cells, where they mediate the transmission of electrochemical signals.
Channel and carrier proteins. (A) Channel proteins form open pores through which molecules of the appropriate size (e.g., ions) can cross the membrane. (B) Carrier proteins selectively bind the small molecule to be transported and then undergo a conformational (more. )
In contrast to channel proteins, carrier proteins selectively bind and transport specific small molecules, such as glucose. Rather than forming open channels, carrier proteins act like enzymes to facilitate the passage of specific molecules across membranes. In particular, carrier proteins bind specific molecules and then undergo conformational changes that open channels through which the molecule to be transported can pass across the membrane and be released on the other side.
As described so far, molecules transported by either channel or carrier proteins cross membranes in the energetically favorable direction, as determined by concentration and electrochemical gradients𠅊 process known as passive transport. However, carrier proteins also provide a mechanism through which the energy changes associated with transporting molecules across a membrane can be coupled to the use or production of other forms of metabolic energy, just as enzymatic reactions can be coupled to the hydrolysis or synthesis of ATP. For example, molecules can be transported in an energetically unfavorable direction across a membrane (e.g., against a concentration gradient) if their transport in that direction is coupled to ATP hydrolysis as a source of energy𠅊 process called active transport (Figure 2.51). The free energy stored as ATP can thus be used to control the internal composition of the cell, as well as to drive the biosynthesis of cell constituents.
Model of active transport. Model of active transportEnergy derived from the hydrolysis of ATP is used to transport H + against the electrochemical gradient (from low to high H + concentration). Binding of H + is accompanied by phosphorylation of the carrier (more. )
Second messengers are of such significance that they need a closer appearance. You will discover this info important for your later understanding of hormone and neurotransmitter action. Let’s try and understand how the hormone epinephrine promotes a cell. Epinephrine, the “very first messenger” can not go through the plasma membrane, so it binds to a surface receptor. The receptor is connected on the intracellular side to a peripheral protein called a G-protein. G proteins are called for the ATP-like chemical, guanosine triphosphate (GTP), from which they get their energy.
When triggered by the receptor, a G protein passes on the signal to another membrane protein, adenylate. Adenylate cyclase eliminates 2 phosphate groups from ATP and transforms it to cyclic AMP (cAMP), the 2nd messenger. Cyclic AMP then triggers enzymes called kinases in the cytosol. Kinases include phosphate groups to other cellular enzymes. This triggers some enzymes and shuts down others, however, in either case, it sets off a fantastic range of physiological modifications within the cell. As much as 60% of presently utilized drugs work by modifying the activity of G proteins.
Structure of a Phospholipid Molecule
A phospholipid is an amphipathic molecule which means it has both a hydrophobic and a hydrophilic component. A single phospholipid molecule has a phosphate group on one end, called the &ldquohead,&rdquo and two side-by-side chains of fatty acids that make up the lipid &ldquotails. &rdquo The phosphate group is negatively charged, making the head polar and hydrophilic, or &ldquowater loving.&rdquo The phosphate heads are thus attracted to the water molecules in their environment.
The lipid tails, on the other hand, are uncharged, nonpolar, and hydrophobic, or &ldquowater fearing.&rdquo A hydrophobic molecule repels and is repelled by water. Some lipid tails consist of saturated fatty acids and some contain unsaturated fatty acids. This combination adds to the fluidity of the tails that are constantly in motion.
Why lipophilic molecules can pass phospholipid bilayer, in spite of 2 hydrophilic layers? - Biology
Review of Membrane Structure
- The plasma membrane plays a crucial role in the function of cells and in the life processes of organisms.
form a hydrophobic barrier at the the periphery.
- How do phospholipids react in an aqueous environment to form a bilayer membrane?
- Why are membrane proteins so important and how are they positioned within a membrane?
How Do Molecules Cross the Plasma Membrane?
- The plasma membrane is selectively permeable hydrophobic molecules and small polar molecules can diffuse through the lipid layer, but ions and large polar molecules cannot.
- Proteins which form channels may be utilized to enable the transport of water and other hydrophilic molecules these channels are often gated to regulate transport rate.
- The process of exocytosis expels large molecules from the cell and is used for cell secretion.
BINDING OF CHOLESTEROL AND ADRENODOXIN TO PHOSPHOLIPID VESICLE-RECONSTITUTED P-450scc*
This chapter examines binding of cholesterol and adrenodoxin to phospholipid vesicle -reconstituted P-450 SCC. The side-chain cleavage of cholesterol requires 3 protein components: (1) cytochrome P-450SCC, (2) adrenodoxin reductase (AR), and (3) adrenodoxin (ADX). The cytochrome catalyses a triple hydroxylation of cholesterol causing the scission of the 20–22 bond the FAD-protein (AR) and the iron sulfur protein (ADX) serve as an electron transport chain to P-450. The chapter discusses the mechanism by which these proteins transfer electrons is investigated: AR forms a complex with ADX the AR receives an electron pair from NADPH and transfers one electron to ADX. Reduction of ADX induces dissociation of the complex and allows interaction of the ADX with cytochrome—simultaneous interaction of ADX with AR and cytochrome does not occur. Binding of cholesterol to cytochrome induces a 20-fold increase in the binding of ADX and vice versa. These studies proposed that mutually facilitated binding of components prevents cytochrome P-450 from functioning as a futile NADPH or adrenodoxin oxidase.