Phospholipids apolar

Lipoproteins. A lipoprotein is an endogenous macromolecule consisting of an inner apolar core of cholesteryl esters and triglycerides surrounded by a monolayer of phospholipid embedded with cholesterol and apoproteins. The functions of lipoproteins are to transport lipids and to mediate lipid metabolism. There are four main types of lipoproteins (classified based on their flotation rates in salt solutions) chylomicrons, very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). These differ in size, molecular weight, and density and have different lipid, protein, and apoprotein compositions (Table 11). The apoproteins are important determinants in the metabolism of lipoproteins—they serve as ligands for lipoprotein receptors and as mediators in lipoproteins interconversion by enzymes. 

Considering only the lipid phase as the transport pathway for the peptide, as the solute enters and diffuses across the membrane it will encounter a number of different microenvironments. The first is the aqueous membrane interface (Fig. 23). In this region, the hydrated polar headgroups of the membrane phospholipids separate the aqueous phase from the apolar membrane interior. It has been shown that this region is capable of satisfying up to 70% of the hydrophobic effect... 

Figure 23 Representation of a cell membrane according to the fluid mosaic model (Singer, 1974). In this model, the aqueous phospholipid interfacial microdomain separates the water compartment from the apolar membrane interior. [Redrawn from Burton et al. (1992) with permission from the publisher.]...

The hydrophobic interior of the phospholipid membrane constitutes a diffusion barrier virtually impermeable for charged particles. Apolar particles, however, penetrate the membrane easily. This is of major importance with respect to the absorption, distribution, and elimination of drugs. 

Most local anesthetics exist in part in the cationic amphiphilic form (cf. p. 208). This physicochemical property favors incorporation into membrane interphases, boundary regions between polar and apolar domains. These are found in phospholipid membranes and also in ion-channel proteins. Some evidence suggests that Na+-channel blockade results from binding of local anesthetics to the channel protein. It appears certain that the site of action is reached from the cytosol, implying that the drug must first penetrate the cell membrane (p. 206). 

Molecules that contain both polar and apolar groups are called amphipathic or amphiphilic. This group includes soaps (see p.48), phospholipids (see p. 50), and bile acids (see p. 56). 

Figure 1. Various physical states of phospholipids in aqueous solution. Note the following features (a) phospholipids residing at the air/water interface are arranged such that their polar head groups maximize contact with the aqueous environment, whereas apolar side chains extend outward toward the air (b) solitary phospholipid molecules remain in equilibrium with various monolayer and bilayer structures (c) bilayer vesicles and micelles remain in equilibrium with solitary phospholipid molecules, provided that the total lipid content exceeds the critical micelle concentration.

Interpretation of the Calorimetric Results. There is little doubt that the transition observed in M. laidlawii membranes arises from the lipids since it occurs at the same temperature in both intact membranes and in water dispersions of membrane lipids. It is reasonable to conclude that in both membranes and membrane lipids the lipid hydrocarbon chains have the same conformation. The lamellar bilayer is well established for phospholipids in water (I, 20, 29) at the concentration of lipids used in these experiments. In the phase change the hydrocarbon core of the bilayer undergoes melting from a crystalline to a liquid-like state. Such a transition, like the melting of bulk paraffins, involves association between hydrocarbon chains and would vanish or be greatly perturbed if the lipids were apolarly bound to protein. We can reasonably conclude that most of the lipids in M. laidlawii membranes are not apolarly bound to protein. 

A more complex case is the serum lipoprotein (74), shown in Figure 13. When sonicated into water, total lipids from both the low density (/ ) and high density (a) lipoproteins give rise to the high resolution spectra expected of molecules which have a high degree of motion. The spectra of the native lipoproteins show line widths nearly identical to those of the lipids alone, so that no additional motional constraints of the apolar portions of the phospholipids occur when the lipids are bound to the apoproteins of the blood lipoproteins. All the obvious peaks observed in the native lipoproteins can be accounted for by lipid protons, and no upheld shift of the methylene protons occurs. We can conclude that unlike the case of the lysolecithin-serum albumin system, the bonding of lipids to proteins is not apolar. In the serum lipoproteins the NMR results are consistent with a micellar structure and not with extensive apolar association of lipid with protein. 

The interactions of TDZ (6) with model membranes composed of different phospholipids were also studied by the same group [78]. Calorimetric studies demonstrated that TDZ (6) altered the thermotropic properties of negatively charged DMPC membranes to a larger extent than of zwitterionic phospholipids (PC and PE). The character of the drug-induced changes of the transition parameters of all studied lipids indicated that TDZ (6), similarly to other phenothiazine derivatives, was likely to be localized close to the po-lar/apolar interface of the bilayers. Experiments in which fluorescent probe 1,6-diphenyl-1,3,5-hexatriene (DPH) was employed revealed that TDZ (6) reduced the mobility of lipid molecules in a concentration-dependent manner and thus decreased membrane fluidity. The influence of TDZ (6) on isolated... 

Because of the unique structure of a lipoid matrix consisting of phospholipids and embedded proteins, the interaction of drag molecules with polar head groups, apolar hydrocarbons, or both, can induce several changes in the membrane. Consequently, the drag behavior is changed (diffusion, accumulation, and conformation) [136]. 

Figure 11.9. Contrast formation in cryo-TEM. (a) Schematic image of a vesicle formed with phospholipid molecules, (b) Schematic representation of a phospholipid molecule with polar headgroup and apolar tail. (c)(d) Projection of the polar head group, which is the strongest scattering center, (e) Calculated line scan considering the projection of the polar head groups, (d) Schematic image of a vesicle. (e)(f) Experimental images of vesicles where the double layer with a thickness of about 3.5 nm is clearly seen. Adapted from Sagalowicz et al. 2003.

Although studies of the thermotropic phase behavior of singlecomponent multilamellar phospholipid vesicles are necessary and valuable, these systems are not realistic models for biological membranes that normally contain at least several different types of phospholipids and a variety of fatty acyl chains. As a first step toward understanding the interactions of both the polar and apolar portions of different lipids in mixtures, DSC studies of various binary and ternary phospholipid systems have been carried out. Phase diagrams can be constructed by specifying the onset and completion temperatures for the phase transition of a series of mixtures and by an inspection of the shapes of the calorimetric traces. A comparison of the observed transition curves with the theoretical curves supports... 

In this work, we will mainly focus on DMPC and DMPG lipids but some other phospholipids work as well. However, if the geometry of a phospholipid molecule (i.e., the contribution of the polar headgroup versus the apolar part - see ref (22, 23)) does not allow the formation of small unilamellar vesicles it will be difficult to generate stable MLs. For instance, in selected experimental conditions, pure phosphatidyletha-nolamine membranes are known to be destabilized (24). 

These experiments have not demonstrated that the conformational preferences of signal sequences are important to their ability to export proteins. To address this problem, we synthesized the family of E. coli K-receptor protein wild-type and mutant signal sequences (shown in Fig. 5 and described in Section III,H) and determined their conformations in various polar and apolar environments by CD (Briggs and Gierasch, 1984 Briggs, 1986). The solvents for these experiments included aqueous buffer and TFE, as described above. In addition, sodium dodecyl sulfate (SDS) micelles and phospholipid vesicles were used as membrane model systems. 

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