Studies Of The Behaviour Of Lipophilic Molecules In Model Membranes: Applications To Amphotericin B And Glycosphingolipids

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Hamilton, Katherine S
Chemistry; Biochemistry
thesis / dissertation description
Our investigations have focused on two model membrane systems: liposomal amphotericin B and glycosphingolipids as minor components in phospholipid bilayers. Although amphotericin B and glycosphingolipids have very diverse biological functions, studying their respective behaviour and interactions in the context of a lipid bilayer is of prime importance.;The association of amphotericin B with lipid vesicles has proven to be a successful modality of treatment, with an antifungal activity that is closely tied to the physical nature (e.g. vesicle size and lipid composition) of the preparation. Using freeze-fracture electron microscopy, density gradient ultracentrifugation, and differential scanning calorimetry we have characterised the basic physical properties and studied features of drug-lipid association in various host matrices. The clinically successful matrix of 7:3 dimyristoyl phosphatidylcholine/dimyristoyl phosphatidylglycerol was compared to representative matrices of saturated and unsaturated phospholipids. The acquired data suggest that for the three lipid types studied, there is aggregation of drug in the bilayer into domains of drug enrichment which coexist with domains low in drug content.;Glycosphingolipids are essential components of eukaryotic cell membranes and have been implicated as modulators of membrane structural properties and sites of recognition at the cell surface. We have used deuterium NMR spectroscopy to study the behaviour of a variety of specifically deuterated glycosphingolipids in model membranes. We have demonstrated that there is very little influence of headgroup structure on glycosphingolipid behaviour and conformation at the level of carbon 2 of the glycolipid fatty acid, and that the proposed features of the x-ray structure of glycosphingolipids (I. Pascher and S. Sundell (1977) Chem Phys Lipids 20, 175-191) also apply to conditions of a fluid membrane environment. The influence of glycosphingolipid fatty acid chain length and phospholipid host matrix chain length were investigated since these factors are thought to regulate glycolipid antigenicity (C. R. Alving and R. L. Richards (1977) Immunochem 14, 373-381; C. R. Alving et al., (1980) Biochem Biophys Acta 600, 117-125). While spectra of the 24 carbon and 18 carbon species of galactosyl ceramide were basically similar, there was evidence of slightly greater motion of the longer chain species. Whole-body motion of the glycosphingolipids was sensitive to temperature and host matrix properties.