Biomedical subjects

M J Zuckermann

Publications and source records attributed to M J Zuckermann.

10 recordsLinked to original sources

PubMed1992

The permeability and the effect of acyl-chain length for phospholipid bilayers containing cholesterol: theory and experiment.

The model of Cruzeiro-Hansson et al. (Biochim. Biophys. Acta (1989) 979, 166-1176) for lipid-cholesterol bilayers at low cholesterol concentrations is used to predict the thermodynamic properties and the passive ion permeability of lipid bilayers as a function of acyl-chain length and cholesterol concentration. Numerical simulations based on the Monte Carlo method are used to determine the equilibrium state of the system near the main gel-fluid phase transition. The permeability is calculated using an ansatz which relates the passive permeability to the amount of interfaces formed in the bilayer when cholesterol is present. The model predicts at low cholesterol contents an increase in the membrane permeability in the transition region both for increasing cholesterol concentration and for decreasing chain length at a given value of the reduced temperature. This is in contrast to the case of lipid bilayers containing high cholesterol concentrations where the cholesterol strongly suppresses the permeability. Experimental results for the Na+ permeability of C15PC and DPPC (C16PC) bilayers containing cholesterol are presented which confirm the theoretical predictions at low cholesterol concentrations.

Algorithms↗

PubMed1991

The effects of density fluctuations on the partitioning of foreign molecules into lipid bilayers: application to anaesthetics and insecticides.

An extensive computer-simulation study is performed on a simple but general molecular model recently proposed (Jørgensen et al. (1991) Biochem. Biophys. Acta 1062, 277-238) to describe foreign molecules interacting with lipid bilayers. The model is a multi-state lattice model of the main bilayer transition in which the foreign molecules are assumed to intercalate at interstitial lattice positions. Specific as well as non-specific interactions between the foreign molecules and the lipid acyl chains are considered. Particular attention is paid to the fluctuating properties of the membrane and how the presence of the foreign molecules modulates these fluctuations in the transition region. By means of computer-stimulation techniques, a detailed account is given of the macroscopic as well as microscopic consequences of the fluctuations. The macroscopic consequences of the fluctuations are seen in the thermal anomalies of the specific heat and the passive trans-membrane permeability. Microscopically, the fluctuations manifest themselves in lipid-domain formation in the transition region which implies an effective dynamic membrane heterogeneity. Within the model it is found that certain anaesthetics and insecticides which are characterised by specific interactions with the lipids have a strong effect on the heterogeneity of the membrane inducing regions of locally very high concentration of the foreign molecules. This leads to a broadening of the specific heat peak and a maximum in the membrane/water partition coefficient. These results are in accordance with available experimental data for volatile general anaesthetics like halothane, local anaesthetics like cocain derivatives, and insecticides like lindane.

Anesthetics↗

PubMed1991

Molecular organization and stability of hydrated dispersions of headgroup-modified phosphatidylethanolamine analogues.

Measurements of the thermotropic behavior of various headgroup-modified analogues of 1-palmitoyl-2-oleoylphosphatidylethanolamine (POPE) and of the ion-triggered destabilization of unilamellar vesicles containing these species have been correlated with X-ray diffraction measurements of the organization of hydrated dispersions of these analogues in the absence and presence of dodecane. The hexagonal II lattice repeat dimension -dhex for dodecane-supplemented dispersions, which reflects the optimal or "spontaneous" radius of surface curvature of the phospholipid component, is increased relative to POPE for most analogues with N-alkyl substitutents or increased amino-to-phosphate group separations. Interestingly, however, POPE analogues that are alkylated on C-1 or C-2 of the ethaolamine group show smaller -dhex values (and hence smaller spontaneous radii of surface curvature) than does POPE itself, despite the greater steric bulk of their headgroups. The lamellar-to-hexagonal II transition temperatures of the various POPE analogues and their abilities to promote contact-dependent vesicle destabilization both show strong correlations with the analogues' measured -dhex values (and hence with their spontaneous radii of curvature). The uniformity of these correlations over a wide range of headgroup structures strongly supports, and may help to refine, recent theories which postulate that the spontaneous surface curvature of a lipid or lipid mixture is a central, quantitative determinant of its tendency to adopt nonlamellar phases and to undergo contact-dependent bilayer destabilization.

Calorimetry↗

PubMed1991

A general model for the interaction of foreign molecules with lipid membranes: drugs and anaesthetics.

A general microscopic interaction model is proposed to describe the changes in the physical properties of phospholipid bilayer membranes due to foreign molecules which, to different degrees, partition between the membrane phases and the aqueous environment. The model is a multi-state lattice model for the main phase transition of lipid bilayers and the foreign molecules are assumed to intercalate as interstitials in the lattice. By varying the model parameters, the diversity in the thermodynamic properties of the model is explored using computer-simulation techniques which faithfully take account of the thermal fluctuations. The calculations are performed in both the canonical and the grand canonical ensembles corresponding to the cases where the concentration of foreign molecules in the membrane is either fixed or varies as the external conditions are changed. A classification of the diverse thermal behaviour, specifically with regard to the phase diagram, the specific heat, the density fluctuations, and the partition coefficient, is suggested with a view to rationalizing a large body of experimental measurements of the effects of different foreign molecules on membrane properties. The range of foreign molecules considered includes compounds as diverse as volatile general anaesthetics like halothane, cocaine-derived local anaesthetics like procaine, calcium-channel blocking drugs like verapamil, antidepressants like chlorpromazine, and anti-cancer agents like adriamycin.

Anesthetics↗

PubMed1991

Anesthetics affect membrane heterogeneity.

A computer-simulation study is performed on a simple but general molecular model of the interaction of general and local anesthetics with lipid membranes. In the neighborhood of the gel-to-fluid membrane phase transition it is found that anesthetics have a strong effect on the heterogeneity of the membrane-inducing regions of locally high anesthetics concentration. This leads to a broadening of the specific heat peak and a maximum in the membrane/water partition coefficient. These results are in accordance with available experimental data for volatile general anesthetics like halothane and local anesthetics like cocaine derivatives.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed1990

Erythrocyte shape simulation by numerical optimization.

In a recent paper we examined the morphology of erythrocytes in terms of the mean mean curvature (MMC) of their cell membranes. A computer simulation of these shapes based on the different geometries showed that the MMC increased from the sphero-stomatocyte to the spheroechinocyte via the discocyte. In this work we extend this analysis by using a numerical optimization method based on importance sampling and the principle of adiabatic cooling. The erythrocyte membrane is treated as a single closed fluid lamina exhibiting viscoelastic characteristics. The energy function of the lamina includes the following terms: (i) Curvature-elastic energy terms which depend on both local and global curvature. (ii) A term describing the compression elasticity of the lamina. (iii) A term which depends on the volume of the cell and which is related to the osmotic pressure across the membrane. In the simulation the cell is assumed to have axial symmetry and it can therefore be described by a finite set of conic sections. So far we have been able to obtain an energy minimum corresponding to a discocyte shape using a sphere as the initial configuration. Our results therefore imply that the well-known sequence of erythrocyte shapes could solely be governed by the above mentioned properties of an ideal fluid forming a closed singly connected lamina.

Blood Viscosity↗

PubMed1989

Theory of thermal anomalies in the specific heat of lipid bilayers containing cholesterol.

A theoretical explanation of the experimentally observed characteristic thermal anomalies in the specific heat of lipid bilayers containing cholesterol is provided in terms of the phase equilibria in the phosphatidylcholine-cholesterol system. The phase equilibria are calculated via a microscopic interaction model that takes proper account of both the conformational and the crystalline degrees of freedom of the lipid acyl chains. It is shown that the characteristic double-peaked specific heat, with a narrow and a broad component, is a natural consequence of the topology of the phase diagram. Some results for the enthalpy of the mixed system are also reported. It is suggested that there is no need for invoking special mechanisms such as lipid-cholesterol complexing or formation of special interfacial regions in the bilayer in order to explain the specific-heat anomalies.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed1988

Interactions of cationic lipid vesicles with negatively charged phospholipid vesicles and biological membranes.

Lipid vesicles with a positive surface charge have been prepared by using mixtures of phosphatidylethanolamine (PE) and phosphatidylcholine (PC) together with low mole fractions of a cationic lipid analogue, 1,2-bis(oleoyloxy)-3-(trimethylammonio)propane (DOTAP). We have used measurements of vesicle aggregation, lipid mixing, contents mixing, and contents leakage to examine the interactions between these vesicles and similar vesicles that carry a negative surface charge. Mixtures of vesicles with opposite surface charges aggregate readily at physiological or lower ionic strengths, and the extent of this aggregation is enhanced for vesicles that contain high proportions of PE relative to PC. Mixing of lipids and aqueous contents can also be observed between such vesicles, particularly when the vesicles contain substantial proportions of PE. Surprisingly, these latter processes are strongly promoted by monovalent salts and do not proceed at very low ionic strengths. PE/DOTAP vesicles show substantial lipid mixing with negatively charged vesicles containing high proportions of phosphatidylcholine, as well as with human erythrocyte ghosts, on a time scale of a few minutes. These interactions are strongly promoted both by the presence of high levels of PE in the cationic vesicles and by the presence of complementary surface charges on the two membrane populations.

Cations↗

PubMed1987

Phase equilibria in the phosphatidylcholine-cholesterol system.

A thermodynamic and a microscopic interaction model are proposed to describe the phase equilibria in the phosphatidylcholine-cholesterol system. The model calculations allow for a solid phase with conformationally ordered acyl chains and liquid phases with conformationally ordered as well as disordered chains. The resulting phase diagram is in excellent agreement with the experimental phase diagram for dipalmitoylphosphatidylcholine bilayers with cholesterol as determined by a recent NMR and calorimetry study. It is thus demonstrated that the phase behaviour of phosphatidylcholine-cholesterol mixtures can be rationalized using only a few basic assumptions: (i) Cholesterol interacts favourably with phosphatidylcholine chains in an extended conformation, (ii) the main transition of pure phosphatidylcholine bilayers takes place in terms of translational variables as well acyl-chain conformational variables, and (iii) cholesterol disturbs the translational order in the crystalline (gel) state of phosphatidylcholine. These results suggest that the occurrence of specific phosphatidylcholine-cholesterol complexes is not implied by the experimental thermodynamic data.

Chemical Phenomena↗

PubMed1985

Softening of lipid bilayers.

The softening of wet lipid bilayer membranes during their gel-to-fluid first-order phase transition is studied by computer simulation of a family of two-dimensional microscopic interaction models. The models include a variable number, q, of lipid chain conformational states, where 2 less than or equal to q less than or equal to 10. Results are presented as functions of q and temperature for a number of bulk properties, such as internal energy, specific heat, and lateral compressibility. A quantitative account is given of the statistics of the lipid clusters which are found to form in the neighborhood of the transition. The occurrence of these clusters is related to the softening and the strong thermal density fluctuations which dominate the specific heat and the lateral compressibility for the high-q models. The cluster distributions and the fluctuations behave in a manner reminiscent of critical phenomena and percolation. The findings of long-lived metastable states and extremely slow relaxational behavior in the transition region are shown to be caused by the presence of intermediate lipid chain conformational states which kinetically stabilize the cluster distribution and the effective phase coexistence. This has as its macroscopic consequence that the first-order transition appears as a "continuous" transition, as invariably observed in all experiments on uncharged lecithin bilayer membranes. The results also suggest an explanation of the non-horizontal isotherms of lipid monolayers. Possible implications of lipid bilayer softening and enhanced passive permeability for the functioning of biological membranes are discussed.

Gels↗