Permeability, lipid bilayers

In special cases (as in colloidal solutions) some particles can be considered as essential and other particles as irrelevant , but in most cases the essential space will itself consist of collective degrees of freedom. A reaction coordinate for a chemical reaction is an example where not a particle, but some function of the distance between atoms is considered. In a simulation of the permeability of a lipid bilayer membrane for water [132] the reaction coordinate was taken as the distance, in the direction perpendicular to the bilayer, between the center of mass of a water molecule and the center of mass of the rest of the system. In proteins (see below) a few collective degrees of freedom involving all atoms of the molecule, describe almost all the... 

Figure 41-6. Permeability coefficients of water, some ions, and other small molecules in lipid bilayer membranes. Molecules that move rapidly through a given membrane are said to have a high permeability coefficient. (Slightly modified and reproduced, with permission, from Stryer L Biochemistry, 2nd ed. Freeman, 1981.)...

Liposomes, which are lipid bilayer vesicles prepared from mixtures of lipids, also provide a useful tool for studying passive permeability of molecules through lipid. This system has, for example, been used to demonstrate the passive nature of the absorption mechanism of monocarboxylic acids [131]. Liposome partitioning of... 

The lipophilicity of a solute affects its permeability in lipid bilayers. Lipophilicity is usually expressed in terms of its partitioning between water and an organic solvent, such as olive oil [95], oleyl alcohol [96], ether [97], or octanol [98]. Partition coefficient (PC) of a compound is expressed as its concentration ratio between organic medium and water at equilibrium ... 

It is well known that the permeabilities across biological membranes and model lipid bilayers strongly depend on both the degree of lipid chain packing in the membranes... 

The difficulties in investigating the influence of permeant size on permeability arise from the fact that changes in permeant size are usually accompanied by changes in lipophilicity, with the latter effects often overshadowing the effects of permeant size alone. Xiang and Anderson studied the effects of lipid chain packing and permeant size and shape on permeability across lipid bilayers [163]. They carried out the experiments in gel... 

FIG. 14 A model for the uptake of weakly basic compounds into lipid bilayer membrane (inside acidic) in response to the pH difference. For compounds with appropriate pki values, a neutral outside pH results in a mixture of both the protonated form AH (membrane impermeable) and unprotonated form A (membrane permeable) of the compound. The unprotonated form diffuse across the membrane until the inside and outside concentrations are equal. Inside the membrane an acidic interior results in protonation of the neutral unprotonated form, thereby driving continued uptake of the compound. Depending on the quantity of the outside weak base and the buffering capacity of the inside compartment, essentially complete uptake can usually be accomplished. The ratio between inside and outside concentrations of the weakly basic compound at equilibrum should equal the residual pH gradient. 

Effect of Cholesterol. Cholesterol inclusion into the lipid bilayers composed of DPPC or DSPC, eliminates apparent Tc and reduces permeability at and above the usual Tc. On the other hand, cholesterol inclusion increases packing of fluid bilayer composed of lipids with unsaturated fatty acyl chains. Since cholesterol rich liposomes are stable in plasma, cholesterol is commonly used as a liposomal component. 

It is difficult to prove that quaternary ammonium compounds can cross lipid bilayers using cell uptake experiments, since several mechanisms may be operative, and separating contributions from each may be very difficult [1]. It may be an advantage to use PAMPA to investigate transport properties of permanently ionized molecules. Of all the molecules whose permeabilities were measured under iso-pH conditions in 2% DOPC/dodecane, verapamil, propranolol, and especially quinine seem to partially violate the pH partition hypothesis, as shown in Figs. 7.47a-c. In Fig. 7.47c, the solid line with slope of +1 indicates the expected effective permeability if the pH partition hypothesis were strictly adhered to. As can be seen at pH 4... 

Xiang, T.-X. Anderson, B. D., Development of a combined NMR paramagnetic ion-induced line-broadening dynamic light scattering method for permeability measurements across lipid bilayer membranes, J. Pharm. Sci. 84, 1308-1315 (1995). 

It has been known for some years that gramicidin forms transmembrane ion channels in lipid bilayers and biological membranes and that these channels are assembled from two molecules of the polypeptide 213). The channels are permeable specifically to small monovalent cations [such as H+, Na+, K+, Rb+, Cs+, Tl+, NH4+, CHjNHj, but not (CH3)2NH2+J and small neutral molecules (such as water, but not urea). They do not allow passage of anions or multivalent cations 21 n. 

All four of these helical arrangements could, in principle, provide a channel long enough to span a lipid bilayer and wide enough to permit ion permeability. 

In series with a desolvation energy barrier required to disrupt aqueous solute hydrogen bonds [14], the lipid bilayer offers a practically impermeable barrier to hydrophilic solutes. It follows that significant transepithelial transport of water-soluble molecules must be conducted paracellularly or mediated by solute translocation via specific integral membrane proteins (Fig. 6). Transcellular permeability of lipophilic solutes depends on their solubility in GI membrane lipids relative to their aqueous solubility. This lumped parameter, membrane permeability,... 

The lipid bilayer arrangement of the plasma membrane renders it selectively permeable. Uncharged or nonpolar molecules, such as oxygen, carbon dioxide, and fatty acids, are lipid soluble and may permeate through the membrane quite readily. Charged or polar molecules, such as glucose, proteins, and ions, are water soluble and impermeable, unable to cross the membrane unassisted. These substances require protein channels or carrier molecules to enter or leave the cell. 

Passive diffusion through the lipid bilayer of the epithelium can be described using the partition coefficient between octanol/water (log P) and A log P (the difference between the partition into octanol/water and heptane/ethylene glycol or heptane/ octanol) [157, 158], The lipophilicity of the drug (log P) (or rather log D at a certain pH) can easily be either measured or calculated, and is therefore generally used as a predictor of drug permeability. Recently, a method using artificial membrane permeation (PAMPA) has also been found to describe the passive diffusion in a similar manner to the Caco-2 cell monolayers [159]. 

To move through the membrane (change sides or transverse diffusion), a molecule must be able to pass through the hydrophobic portion of the lipid bilayer. For ions and proteins, this means that they must lose their interactions with water (desolvation). Because this is extremely difficult, ions and proteins do not move through membranes by themselves. Small molecules such as C02, NH3 (but not NH ). and water can diffuse through membranes however, most other small molecules pass through the lipid bilayer very slowly, if at all. This permeability barrier means that cells must develop mechanisms to move molecules from one side of the membrane to the other. 

Figure 3. Temperature effects on permeability of calcein through lipid bilayer membranes of Mals(Phyt)2 and DPPC.

Kagan, B.L., et al., Antimicrobial defensin peptides form voltage-dependent ion-permeable channels in planar lipid bilayer membranes, Proc. Natl. Acad. Sci. U. S.A. 87,1,210,1990. 

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