Compositional domain structure in phosphatidylcholine--cholesterol and sphingomyelin--cholesterol bilayers.

Abstract

The lateral distribution of cholesterol in phospholipid bilayers has been investigated through a method of Monte Carlo calculations, using interaction energies deduced from calorimetric results for cholesterol-phospholipid mixtures. Analysis of computer-generated bilayer configurations allows calculation of the spatial localization and relative abundance of distinct regions of varying cholesterol content along the plane of the bilayer. An interfacial phospholipid region between cholesterol-bound and cholesterol-free domains is found to extend one lipid beyond the cholesterol-bound domain for mixtures of cholesterol with palmitoyl sphingomyelin, lignoceroyl sphingomyelin, and dipalmitoyl phosphatidylcholine. The results indicate that the degree of nonideality in the mixing of cholesterol is dependent on fatty acid chain length and that cholesterol mixes more ideally in sphingomyelins than in phosphatidylcholines of equal chain length. It is found that at ;20 mol % cholesterol the cholesterol-rich areas suddenly become connected, forming a network that extends over the entire bila er. This change in the lateral connectivity of the cholesterol-rich domains occurs over a narrow concentration interval and is presumably responsible for the abrupt change in the lateral diffusion coefficient observed at this concentration. In the past few years numerous physical studies have attempted to characterize the interactions of cholesterol with phosphatidylcholines and sphingomyelins (1). These major lipid components have been of interest due to the fundamental role they play in the regulation of the molecular and macroscopic properties of biological membranes. The common elements found in most studies of cholesterol-phospholipid mixtures have been breaks or discontinuities in behavior at concentrations ranging from 7.5 to 50 mol % cholesterol (2). These discontinuities have been interpreted from a molecular point of view, as evidence for the formation of cholesterol-phospholipid complexes of specific stoichiometry (3-5), or from a macroscopic point of view, as an indication of phase boundaries in the construction of phase diagrams for these mixtures (2, 6). Only recently have attempts been made to correlate molecular properties with macroscopic phase behavior from a unified point of view. In this respect, Pink and Chapman (7) successfully predicted the dependence of the transition enthalpy of dipalmitoyl phosphatidylcholine (Pam2-PtdCho) on the mole fraction of cholesterol; however, those mean field calculations were directed towards evaluating overall thermodynamic parameters and as such provided no information regarding the distribution of cholesterol and distinct phospholipid species within the bilayer.In order to fully characterize the interactions of cholesterol with phospholipid bilayers, it will be necessary to develop a quantitative description of the distribution of cholesterol within the bilayer and the relationship of this distribution with ex- (9) have been shown to be composed of broad and sharp componen...

Formulation and characterization of boanmycin-loaded liposomes prepared by pH gradient experimental design

“…Obtained results of CHOL on the EPCS thermotropic behavior are in good agreement with those given in the literature (McMullen and McElhaney, 1995;Matsingou and Demetzos, 2007). Some related research reports that this phase behavior may be explained by a combinative model of 1:1 and 1:2 stoichiometry between CHOL and phospholipids (Presti et al, 1982;Snyder and Freire, 1980). According to this model, one phospholipid is tightly bound to one CHOL molecule through a hydrogen bond between the −OH groups of CHOL and the glycerol ester oxygen of the phospholipid.…”

Superior therapeutic activity of liposome-associated adriamycin in a murine metastatic tumour model

“…However, if therapeutic applications of L-ADM are contemplated, PG should be preferred to PS because it is less sensitive to lipid oxidation processes affecting the head group (Roseman et al, 1975) and can be readily obtained from animal sources by a simpler enzymatic conversion of PC (Comfurius & Zwaal, 1977). The fact that the Chol: phospholipid molar ratio can be decreased to 25% without any significant loss of anti-tumour activity is consistent with the ability of liposomes to withstand the deleterious effect of serum proteins when the Chol content is kept above 20% (Pownall et al, 1979;Snyder & Freire, 1980). This reduction of Chol content is important as it allows to reduce the lipid load necessary to deliver therapeutic doses of ADM.…”

Sphingomyelin and Cholesterol: From Membrane Biophysics and Rafts to Potential Medical Applications

“…These studies show}hat cholesterol when present in a bilayer of phospholipid which undergoes SO to LD phase transition reduces the number of phospholipid molecules participating in the cooperative process of this phase transition in a manner dependent on mole% cholesterol (Rubenstein et al, 1979;Snyder and Freire, 1980;de Kruijff et al, 1985;Small, 1986). When reaching a mole fraction ofapprox.…”

“…Snyder and Freire (1980) suggested a model for predicting the amount of distinct phases of pure phospholipid, of cholesterol-phospholipid mixed domains (cholesterol-rich domains), and of the interphases between them. They also dealt specifically with two SM/cholesterol systems based on fully synthetic D,L-erythro SMs (N-palmitoyl (C16) SM and N-lignoceryl (C24) SM) and compared them with DPPC/Chol.…”