Lipid bilayer of biologic

The lipid bilayer of biological membranes, as discussed in Chapter 12. is intrinsically impermeable to ions and polar molecules. Permeability is conferred by two classes of membrane xoXems, pumps and channels. Pumps use a source of free energy such as ATP or light to drive the thermodynamically uphill transport of ions or molecules. Pump action is an example of active transport. Channels, in contrast, enable ions to flow rapidly through membranes in a downhill direction. Channel action illustrates passive transport, or facilitated diffusion. 

Lipophilicity is a measure of a chemical s affinity for the lipid bilayer of biological membranes. The logarithm of the partition coefficient between water and 1-octanol (log Kow) is used as an indicator of a chemical s lipophilicity. The parabolic relationship between log P and effect can be used as evidence that there are limits to absorption for super-lipophilic compounds , and why these limits exist (20). Chemicals that have log P values greater than 6 tend to dissolve in the non-polar interior of a membrane inhibiting transport. 

What experimental observation shows that proteins diffuse within the lipid bilayers of biological membranes ... 

Although for the moment this model is only partially supported by experimental data it offers the opportunity to design new experiments which will help to understand the mechanisms of pardaxin insertion and pore formation in lipid bilayers and biological membranes which at a molecular level are the events leading to shark repellency and toxicity of this marine toxin. 

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. 

Table 4. Major building blocks of lipid bilayers in biological membranes and their speciation and acidity constants...

In the following section, the role of the various types of complexes mentioned above will be discussed with regard to various mechanisms of interactions at biological interphases. It is clear that metal ions and hydrophilic complexes cannot distribute into the membrane lipid bilayer or cross it. The role of hydrophilic ligands has thus to be discussed in relation to binding of metals by biological ligands. In contrast, hydrophobic complexes may partition into the lipid bilayer of membranes (see below, Section 6). 

We should first emphasize that viscosity is a macroscopic parameter which loses its physical meaning on a molecular scale. Therefore, the term microviscosity should be used with caution, and the term fluidity can be alternatively used to characterize, in a very general way, the effects of viscous drag and cohesion of the probed microenvironment (polymers, micelles, gels, lipid bilayers of vesicles or biological membranes, etc.). 

This permeability barrier shows selectivity in that small hydrophobic molecules can partition into and diffuse across the lipid bilayer of the cell membrane, whereas small hydrophilic molecules can only diffuse between cells (i.e., through the intercellular junctions). In addition, the presence of uptake and efflux transporters complicates our ability to predict intestinal permeability based on physicochemical properties alone because transporters may increase or decrease absorptive flux. The complexity of the permeability process makes it difficult to elucidate permeability pathways in complex biological model systems such as animals and tissues. For this reason, cultured cells in general, and Caco-2 cells in particular, have been used extensively to investigate the role of specific permeability pathways in drug absorption. 

The successful application of in vitro models of intestinal drug absorption depends on the ability of the in vitro model to mimic the relevant characteristics of the in vivo biological barrier. Most compounds are absorbed by passive transcellular diffusion. To undergo tran-scellular transport a molecule must cross the lipid bilayer of the apical and basolateral cell membranes. In recent years, there has been a widespread acceptance of a technique, artificial membrane permeation assay (PAMPA), to estimate intestinal permeability.117118 The principle of the PAMPA is that, diffusion across a lipid layer, mimics transepithelial permeation. Experiments are conducted by applying a drug solution on top of a lipid layer covering a filter that separates top (donor) and bottom (receiver) chambers. The rate of drug appearance in the bottom wells should reflect the diffusion across the lipid layer, and by extrapolation, across the epithelial cell layer. 

The discriminative uptake of alkali metal cations by biological systems, through their membranes, has been an area of much interest. In the membrane, the cations must pass through a lipid bilayer of low dielectric constant and this has led to the proposition that the cation could be selectively transferred via a carrier molecule, or through a suitably donor-lined pore.7-9 As a consequence of their selective properties, the polyethers and cryptands have been investigated as speculative models for the above process and selectivity sequences have been established. 

FIGURE 11-28 Energy changes accompanying passage of a hydrophilic solute through the lipid bilayer of a biological membrane, (a) In... 

As stated, biological membranes are normally arranged as bilayers. It has, however, been observed that some lipid components of biological membranes spontaneously form non-lamellar phases, including the inverted hexagonal form (Figure 1.9) and cubic phases [101]. The tendency to form such non-lamellar phases is influenced by the type of phospholipid as well as by inserted proteins and peptides. An example of this is the formation of non-lamellar inverted phases by the polypeptide antibiotic Nisin in unsaturated phosphatidylethanolamines [102]. Non-lamellar inverted phase formation can affect the stability of membranes, pore formation, and fusion processes. So-called lipid polymorphism and protein-lipid interactions have been discussed in detail by Epand [103]. 

DSC has also been used to study the effects of a wide variety of antimicrobial peptides on the thermotropic phase behavior of different lipid bilayers. These studies again are highly biologically relevant because the primary mode of action of most antimicrobial peptides is the perturbation and permeabilization of the lipid bilayers of the target membrane, and these agents have considerable promise as antibiotics, especially to treat multiple dmg-resistant pathogenic bacteria. Again, the reader should consult recent reviews for more information on this topic (30, 31). 

The characteristics of the water associated with the polar lipid bilayer surfaces are of particular interest because they become very important in processes of physiological significance such as membrane fusion, and they may play a role in the mechanisms of association of proteins and small molecules with lipid bilayers and biological membranes. A very small fraction of the lipid bilayer-associated water molecules are actually immobilized, and a larger fraction (about 30% of the total bilayer-associated water in multilamellar PC bilayers in the L phase) has a probability distribution function that is more or less coincident with the probability distribution function for the polar head group of the lipids. Nevertheless, the pressure, P, which must be exerted to remove the bilayer-associated water, is large and varies (from 0.5-500 N cm ) with the thickness of the inter-bilayer water space as ... 

---