Term
| What are 3 examples of aqueous phases in the body? What are 3 examples of lipoid phases? |
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Definition
Aqueous phases - water in body fluids (GI tract, urine, plasma), interstitial water, intracellular water
Lipoid phases - hydrophobic cores of membranes (bilayers), lipid droplets (lipoproteins), interiors of globular proteins. |
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Term
| What is needed for the proper functioning of metabolism? |
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Definition
| Compartmentalization of intracellular space. |
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Term
Membranes control _____a_____.
Phospholipid bilayers are almost _____b____.
_____c_______ transfer physiologic molecules in the proper direction. |
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Definition
(a) Movement of water-soluble substances (substrates, metabolites, etc.)
(b) impermeable
(c) Protein carriers |
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Term
| What is responsible for the creation of membrane potential? |
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Definition
| The restricted movement of ions through membranes. |
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Term
| Dissolution of the drug molecule in water or in a lipoid phase causes ____. |
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Definition
| changes in both the drug molecule and in the surrounding medium. |
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Term
| What are the surrounding molecules of the medium / solvent classified as? Define each. |
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Definition
Region A (immediate vicinity, contact)
Region B (connecting)
Region C (bulk solvent) |
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Term
| What do structural changes of the medium depend on? |
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Definition
| The type of the parts of the drug molecule (polar, non-polar, ionic). |
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Term
| How many hydrogen bonds can each water molecule form? What are they? |
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Definition
| Each water molecule can form 4 hydrogen bonds. Two as the donor (hydrogens) and 2 as the acceptor (oxygen). |
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Term
| What type of network do the hydrogen bonds form in liquid and solid phases? |
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Definition
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Term
| What could exist in the gas phase? |
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Definition
| Hydrogen bonded dimers and higher aggregates (up to 8 water molecules). |
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Term
| In ice, how many hydrogens is each oxygen surrounded by? Describe the bonds. |
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Definition
| Each oxygen is surrounded by 4 hydrogens. Two connected covalently and two connected by hydrogen bonds. |
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Term
| Describe liquid water. How many hydrogen bonds does it contain at any given moment? |
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Definition
| Liquid water is a non-crystalline random network of hydrogen bonds. At any given moment it contains >50% of all possible hydrogen bonds. |
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Term
| How fast does liquid water transform its hydrogen bond configurations? Describe the tetrahedrality. |
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Definition
| It is continuously transforming on the time scale of 10^-11 - 10^-12 seconds. It's tetrahedrality (HOH) is distorted. |
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Term
| Is the dielectric constant (e) higher for water or for lipoid phases? |
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Definition
| It is much higher for water. |
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Term
| Why is the structure of region A different from region C? |
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Definition
| THe structure of region A is usually different than the structure of region C due to electrostatic interactions depending on the size of the ion. |
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Term
| How much stronger are the electrostatic interactions (in region A) than the interactions among the water molecules? |
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Definition
| The electrostatic interactions are one order of magnitude stronger. |
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Term
What are cations and what are they surrounded by?
What are anions and what are they surrounded by? |
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Definition
Cations are positively charged ions. They are surrounded by the oxygens in water that bear small negative charges.
Anions are negatively charged ions. They are surrounded by the hydrogens in water that bear small positive charges. |
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Term
| What type of ions stabilize the structure of water? Describe them. List some examples. |
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Definition
| Kosmotropic ions stabilize the structure of water. They are anions with high charge densities (small molecule, high charge). Some examples are SO4^-2, HPO4^-2, F^-1, etc. |
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Term
| What type of ions break down the structure of water? Describe them. List some examples. |
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Definition
| Chaotropic ions (think chaos) break down the structure of water. They are anions with small charge densities (big molecule, small charge). Some example are CBr3COO-, I-, Br-, NO3-, etc. |
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Term
| Describe the cooperativity of hydrogen bonds. |
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Definition
| In water, four hydrogen bonds distory the electron distribution as compared with isolated water molecules. Electrons of the oxygen atom are attracted towards the surrounding 4 hydrogen atoms. Interruption of any hydrogen bond (1) increases the electron density of the oxygen atom and (2) strengthens the remaining hydrogen bonds. |
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Term
| Non-polar molecules interrupt the hydrogen bonds between water molecules. What happens to the remaining hydrogen bonds? What do they form and where do they form it? |
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Definition
| The remaining hydrogen bonds get stronger, forming a hydration shell (iceberg sweater) around the apolar molecules. (Region A) |
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Term
| Describe region A in comparison to region C when a hydrophobic molecule interacts with water. |
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Definition
| Water in region A has geometrically the same structure as region c, but the hydrogen bonds are stronger *due to cooperativity*. Therefore, the water molecules are more organized. This is an unfavorable decrease in the entropy of the system. |
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Term
| Why are two non-polar particles held together in water? |
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Definition
| When two non-polar molecules touch in water they form a smaller shell than if they were to be separated. This creates a smaller Region A, which means a smaller decrease in entropy than if they were separated. One hydration shell / iceberg sweater is better than two! |
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Term
| Describe the attractive interaction of two hydrophobic particles in water. |
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Definition
| Not held together because non-polar particles are touching, but rather held together by the surrounding medium. |
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Term
| Describe the solubility of crystals in relation to chaotropic anions and kosmotropic anions. |
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Definition
| Chaotropic anions (structure destabilizing) increase solubility. Kosmotropic anions (structure stabilizing) decrease solubility. |
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Term
| What is the general molecular formula for simple alkyl groups? |
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Definition
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Term
| Name 3 characteristics of the alkyl chains that form the lipoid phases. |
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Definition
(1) Do not form hydrogen bonds.
(2) Do not create electrostatic interactions.
(3) Form dispersion interactions. |
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Term
| Alkyl chains are not ____a___ and are quite ____b____. Are there any major structural changes observed upon solvation? |
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Definition
(a) well organized
(b) quite flexible
No major structural changes observed upon solvation. |
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Term
| Lipoid phases are ___a___ selective in solvation of individual types of molecules. Solubilities of drugs in lipids vary ___b____ than solubilities in water. |
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Definition
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Term
| In water, the non-polar parts of the drug form ___a____ interactions, the polar parts of the drug are ___b____. Why? |
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Definition
(a) hydrophobic - they are in contact
(b) separated. They are separated because the electrostatic interactions are well shielded (water has a high e) and each charged atom si well hydrated. |
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Term
| When are intramolecular hydrogen bonds formed in the drug when in water? |
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Definition
| Intramolecular hydrogen bonds are formed only if they are stronger than competing hydrogen bonds with water. |
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Term
| In lipoid phases, all atoms of drug molecules participate in __a__ interactions. There are no ____b____ interactions. Why? |
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Definition
(a) dispersion (London)
(b) hydrophobic. This is because the nonpolar parts do not form aggregates. |
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Term
| ______ interactions are stronger in lipoid phases than in water. Why? |
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Definition
Electrostatic.
This is because lipoid phases have a smaller dielectric constant than water so they interactions between drug molecules are less shielded. The ions in the drug can "feel" each other on longer distance. |
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Term
| Describe hydrogen bonds in the drug in a lipoid phase. |
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Definition
| If the drug molecule alone can form hydrogen bonds intramolecularly, they are stronger than in water. |
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Term
| Drug molecules can be transported via bilayer in 2 ways. What are they? |
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Definition
Lateral diffusion: diffusion of surfactant-like molecules in the surface of the bilayer.
Trans-bilayer diffusion: crossing the bilayer. |
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Term
| Name the 4 main components of mammalian bilayers. |
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Definition
Phospholipids, sphingomyelins, glycolipids, cholesterol.
Once the main chain melting temperature is reached, the bilayer transforms from a gel state to a fluid state. |
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Term
| Tm is the main chain melting temperature. Most mammalian bilayers have a Tm between _a_ and _b_ degrees celcius. |
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Definition
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Term
| Name 3 things that decrease fluidity at a given temperature. |
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Definition
| Cholesterol, saturated fatty acid chains in phospholipids, rigid hydrophobic molecules that can intercalate between the fatty acid chains. |
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Term
| Name 2 things that increase the fluidity of a bilayer at a given temperature. |
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Definition
| Unsaturated fatty acids and molecules dissolved in the bilayer. |
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Term
| When does the gel phase of a bilayer occur? What are its characteristics? |
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Definition
| The gel phase occurs when the temperature is below Tm. The phospholipid chains are extended and there is tight packing (slow passive transport). |
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Term
| When does the liquid phase of the bilayer occur? What are the 5 characteristics of the liquid phase? |
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Definition
Above Tm.
(1) More conformational freedom.
(2) More movement.
(3) Smaller thickness of the bilayer
(4) larger area per phospholipid
(1-4 = faster passive transport)
(5) more hydration in the headgroup region |
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Term
| When does the fastest passive transport occur? |
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Definition
| The fastest passive transport occurs AT Tm - mixed phases. |
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Term
| What did Nageli discover? |
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Definition
| That osmotic barriers surround the cell content. |
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Term
| What did Wilhelmy discover? |
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Definition
| The measurement of surface tension. |
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Term
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Definition
| Invention of the predecessor of the Langmuir trough. |
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Term
| What did Overton discover? |
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Definition
| Membranes contain lipids. |
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Term
| What did Langmuir design? |
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Definition
| THe structure of air/water monolayer of fatty acids. |
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Term
| What did Gorter and Grendel discover? |
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Definition
| That the membrane includes 2 monolayers. |
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Term
| What did Danielli and Davson discover? |
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Definition
| The membrane consists of lipids held by proteins. |
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Term
| What did Robertson discover? |
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Definition
| The membrane is a self-standing bilayer with adsorbed proteins and that the phospholipid geometry affects the shape of aggregates. |
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Term
| What did Luzzati observe? |
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Definition
| Gel and liquid phases of the bilayer observed by X-ray diffraction. |
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Term
| What did Singer and NIcholson invent? |
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Definition
| Fluid mosaic model of membrane. |
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Term
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Definition
| That proteins interact with the core via hydrophobic residues. |
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Term
| What did Mouritsen observe? |
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Definition
| That lipid secretion around proteins avoids hydrophobic mismatch. |
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Term
| What did Nielsen et al observe? |
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Definition
| AFM observation of coexisting gel and liquid phases. |
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Term
Region 1:
Consists of __a__?
Thickness is __b__?
Describe density - c
How many water molecules per headgroup? - d
The number of water molecules __e__ with temperature? |
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Definition
a - perturbed water; low headgroup density
b - 1nm thick
c - density gradually increases
d - 12-16 water molecules per headgroup just above transition temperature
e - increases |
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Term
Region 2:
Consists of --a--?
Thickness --b--?
Describe density. - c
Just above the transition temperature, all _____ are engaged in ____. |
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Definition
a - headgroup region - high headgroup density
b - 0.8nm
c - the highgest density, the lowest free volume
d - Just above the transition temperatures, all hydrating waters are engaged in hydrogen bonds. |
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Term
Region 3:
a - content
b - thickness
c - density
d - First _______ of the chains. |
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Definition
a - soft polymer - high core density
b - 0.7nm
c - Density lower than in region 2
d - First 6-8 methylene segments of the chains. |
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Term
Region 4:
Content - a
thickness - b
density - c |
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Definition
a - alkanes - low care density
b - thickness depends on length of fatty acid chains
c - density of hexadecane |
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Term
| What is the overall bilayer thickness? Headgroups are formed by which regions? Hydrophobic core is formed by which regions? |
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Definition
| The overall bilayer thickness is 4.5-5.5nm thick. The headgroups are formed by regions 1 and 2. The hydrophobic core is formed by regions 3 and 4. |
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Term
| What molecules can hop between thermal kinks diffuse passively through the bilayer? |
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Definition
| Small nonionized molecules. Ex. water, urea, oxygen, carbon monoxide, carbon dioxide, nitric oxide, nonionized formic acid |
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Term
| What passes through larger, water-filled pores? |
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Definition
| Monovalient ions - proteins, sodium, potassium |
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Term
| What diffuses through a heterogenous bilayer? |
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Definition
Larger molecules (up to 1000g/mol) including most drugs.
Solubility/diffusion mechanism |
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Term
| When is transport across a bilayer fastest? |
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Definition
| Transport is fast for compounds that exhbit intermediate strength of interactions in the headgroup region and in the hydrocarbon core. Any deviation (up or down) from the optimal interaction strength leads to a dramatic decrease in transport rate. |
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Term
| What is the main driving force for self-assembly of phospholipid aggregates in water and non-polar solvents? |
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Definition
Amphiphilicty.
The non-polar parts participate in hydrophobic interactions between themselves or with non-polar solvent.
The polar headgroups form hydrogen bonds and electrostatic interactions between themselves and with water. |
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Term
| What is the shape of a phospholipid molecule made by saturated acyls of fatty acids? |
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Definition
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Term
| What is the shape made by lysoderivites? |
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Definition
| Conical - head bulkier than the tail |
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Term
| What is the shape of phospholipid molecules made by unsaturated Fatty Acids? |
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Definition
| Conical - tail bulkier than head |
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Term
| What are the characteristics of spherical aggregates? |
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Definition
Non-bilayer:
Micelles - In water, headgroups bulkier than tails
Inverted micelles - in non-polar solvents, tails bulkier than headgroups
Bilayer: made by cylindrical phospholipids
Non-supported - liposomes
Supported - on glass, silica, or metals |
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Term
| What are the characteristics of fibrous (rod-like) aggregates? |
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Definition
They fill the entire volume of the vial.
Hexagonal phase I - cross-section as inverted micelles
Hexagonal phase II - cross-section as micelles |
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Term
| What are the characteristics of planar aggregates? |
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Definition
| Large lamellar phases or small discoids. |
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Term
| Describe 3 types of supported spherical aggregates. |
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Definition
(1) bilayer adsorbed on microspheres.
(2) monolayer adsorbed on alkylated microspheres.
(3) phospholipids bound to microspheres. |
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Term
| What are small discoids? Describe 2 types of discoids. |
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Definition
Discoids are planar bilayer aggregates.
(1) nanodiscs - edge stabilized by proteins
(2) bicelles - edge stabilized by short fatty acids. |
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Term
| What are black lipid membranes? |
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Definition
They are large lamellar phases.
On 1mm opening in a Teflon barrier separating 2 compartments.
Planar bilayer sheets filling the entire volume. |
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Term
| Cylindrical phospholipid molecules make what shape at a low phospholipid concentration? At a high phospholipid concentration? |
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Definition
Low - liposomes, uni- and multi-lamellar
High - lamellar phase |
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Term
| Conical (heads bigger than tails) phospholipid molecules make what shape at a low phospholipid concentration? At a high phospholipid concentration? |
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Definition
Low - micelles
High - hexagonal phase II |
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Term
| Conical (tails bulkier than heads) phospholipid molecules make what shape at a low phospholipid concentration? At a high phospholipid concentration? |
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Definition
Low - hexagonal phase I
High - inverted micelles |
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Term
| List 4 ways to prepare liposomes/vesicles (crude formulations). |
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Definition
(1) Sonicaiton of an aqueous phospholipid dispersion.
(2) Injection of an ethanolic solution of phospholipids into water
(3) evaporation of organic solvent (hexane, for example) from its mixture with phospholipids and water.
(4) dialysis of a detergent used to form micelles with phospholipids in water. |
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Term
| List 2 ways to refine or purify liposomes or vesicles. |
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Definition
(1) centrifugation to remove larger particles
(2) extrusion through porous membrane |
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