PubMed Health⌕ Search

Biomedical subjects

O G Mouritsen

Publications and source records attributed to O G Mouritsen.

At least 19 recordsLinked to original sources
PubMed1998

Theoretical analysis of protein organization in lipid membranes.

The fundamental physical principles of the lateral organization of trans-membrane proteins and peptides as well as peripheral membrane proteins and enzymes are considered from the point of view of the lipid-bilayer membrane, its structure, dynamics, and cooperative phenomena. Based on a variety of theoretical considerations and model calculations, the nature of lipid-protein interactions is considered both for a single protein and an assembly of proteins that can lead to aggregation and protein crystallization in the plane of the membrane. Phenomena discussed include lipid sorting and selectivity at protein surfaces, protein-lipid phase equilibria, lipid-mediated protein-protein interactions, wetting and capillary condensation as means of protein organization, mechanisms of two-dimensional protein crystallization, as well as non-equilibrium organization of active proteins in membranes. The theoretical findings are compared with a variety of experimental data.

Animals↗
PubMed1998

Steady-state compartmentalization of lipid membranes by active proteins.

Using a simple microscopic model of lipid-protein interactions, based on the hydrophobic matching principle, we study some generic aspects of lipid-membrane compartmentalization controlled by a dispersion of active integral membrane proteins. The activity of the proteins is simulated by conformational excitations governed by an external drive, and the deexcitation is controlled by interaction of the protein with its lipid surroundings. In response to the flux of energy into the proteins from the environment and the subsequent dissipation of energy into the lipid bilayer, the lipid-protein assembly reorganizes into a steady-state structure with a typical length scale determined by the strength of the external drive. In the specific case of a mixed dimyristoylphosphatidylcholine-distearoylphosphatidylcholine bilayer in the gel-fluid coexistence region, it is shown explicitly by computer simulation that the activity of an integral membrane protein can lead to a compartmentalization of the lipid-bilayer membrane. The compartmentalization is related to the dynamical process of phase separation and lipid domain formation.

Computer Simulation↗
PubMed1998

A new look at lipid-membrane structure in relation to drug research.

Lipid-bilayer membranes are key objects in drug research in relation to (i) interaction of drugs with membrane-bound receptors, (ii) drug targeting, penetration, and permeation of cell membranes, and (iii) use of liposomes in micro-encapsulation technologies for drug delivery. Rational design of new drugs and drug-delivery systems therefore requires insight into the physical properties of lipid-bilayer membranes. This mini-review provides a perspective on the current view of lipid-bilayer structure and dynamics based on information obtained from a variety of recent experimental and theoretical studies. Special attention is paid to trans-bilayer structure, lateral molecular organization of the lipid bilayer, lipid-mediated protein assembly, and lipid-bilayer permeability. It is argued that lipids play a major role in lipid membrane-organization and functionality.

Animals↗
PubMed1997

Phase behavior and permeability properties of phospholipid bilayers containing a short-chain phospholipid permeability enhancer.

The thermodynamic phase behavior and trans-bilayer permeability properties of multilamellar phospholipid vesicles containing a short-chain DC10PC phospholipid permeability enhancer have been studied by means of differential scanning calorimetry and fluorescence spectroscopy. The calorimetric scans of DC14PC lipid bilayer vesicles incorporated with high concentrations of DC10PC demonstrate a distinct influence on the lipid bilayer thermodynamics manifested as a pronounced freezing-point depression and a narrow phase coexistence region. Increasing amounts of DC10PC lead to a progressive lowering of the melting enthalpy, implying a mixing behavior of the DC10PC in the bilayer matrix similar to that of a substitutional impurity. The phase behavior of the DC10PC-DC14PC mixture is supported by fluorescence polarization measurements which, furthermore, in the low-temperature gel phase reveal a non-monotonic concentration-dependent influence on the structural bilayer properties; small concentrations of DC10PC induce a disordering of the acyl chains, whereas higher concentrations lead to an ordering. Irreversible fluorescence quench measurements demonstrate a substantial increase in the trans-bilayer permeability over broad temperature and composition ranges. At temperatures corresponding to the peak positions of the heat capacity, a maximum in the trans-bilayer permeability is observed. The influence of DC10PC on the lipid bilayer thermodynamics and the associated permeability properties is discussed in terms of microscopic effects on the lateral lipid organization and heterogeneity of the bilayer.

Calorimetry, Differential Scanning↗
PubMed1997

The effects of ethylene oxide containing lipopolymers and tri-block copolymers on lipid bilayers of dipalmitoylphosphatidylcholine.

A comparative study is conducted on the influence of two types of polymeric compounds on the phase behavior of 1,2-dihexadecanoyl-s,n-glycero-3-phosphotidylcholine (DC16PC) lipid bilayers. The first polymeric compound is a lipopolymer, with two different lengths of a hydrophilic polyethylene oxide moity, anchored to the bilayer by a 1,2-dioctadecanoyl-s,n-glycero-3-phosphoethanolamine (DC18PE) lipid. The second type, which is a novel type of membrane-spanning object, is an amphiphilic tri-block copolymer composed of two hydrophilic stretches of polyethylene oxide separated by a hydrophobic stretch of polystyrene. Hence the tri-block copolymer may act as a membrane-spanning macromolecule mimicking an amphiphilic protein or polypeptide. Differential scanning calorimetry is used to determine a partial phase diagram for the lipopolymer systems and to assess the amount of lipopolymer that can be loaded into DC16PC lipid bilayers before micellization takes place. Unilamellar and micellar phase structures are investigated by fluorescence quenching using bilayer permeating dithionite. The chain length-dependent critical lipopolymer concentration, denoting the lamellar-to-micellar phase transition, compares favorably with a theoretical prediction based on free-energy considerations involving bilayer cohesion and lateral pressure exerted by the polymer chains.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1997

Wetting and capillary condensation as means of protein organization in membranes.

Wetting and capillary condensation are thermodynamic phenomena in which the special affinity of interfaces to a thermodynamic phase, relative to the stable bulk phase, leads to the stabilization of a wetting phase at the interfaces. Wetting and capillary condensation are here proposed as mechanisms that in membranes may serve to induce special lipid phases in between integral membrane proteins leading to long-range lipid-mediated joining forces acting between the proteins and hence providing a means of protein organization. The consequences of wetting in terms of protein aggregation and protein clustering are derived both within a simple phenomenological theory as well as within a concrete calculation on a microscopic model of lipid-protein interactions that accounts for the lipid bilayer phase equilibria and direct lipid-protein interactions governed by hydrophobic matching between the lipid bilayer hydrophobic thickness and the length of the hydrophobic membrane domain. The theoretical results are expected to be relevant for optimizing the experimental conditions required for forming protein aggregates and regular protein arrays in membranes.

Biophysical Phenomena↗
PubMed1997

Molecular sorting of lipids by bacteriorhodopsin in dilauroylphosphatidylcholine/distearoylphosphatidylcholine lipid bilayers.

A combined experimental and theoretical study is performed on binary dilauroylphosphatidylcholine/distearoylphosphatidylcholine (DLPC/DSPC) lipid bilayer membranes incorporating bacteriorhodopsin (BR). The system is designed to investigate the possibility that BR, via a hydrophobic matching principle related to the difference in lipid bilayer hydrophobic thickness and protein hydrophobic length, can perform molecular sorting of the lipids at the lipid-protein interface, leading to lipid specificity/selectivity that is controlled solely by physical factors. The study takes advantage of the strongly nonideal mixing behavior of the DLPC/DSPC mixture and the fact that the average lipid acyl-chain length is strongly dependent on temperature, particularly in the main phase transition region. The experiments are based on fluorescence energy transfer techniques using specifically designed lipid analogs that can probe the lipid-protein interface. The theoretical calculations exploit a microscopic molecular interaction model that embodies the hydrophobic matching as a key parameter. At low temperatures, in the gel-gel coexistence region, experimental and theoretical data consistently indicate that BR is associated with the short-chain lipid DLPC. At moderate temperatures, in the fluid-gel coexistence region, BR remains in the fluid phase, which is mainly composed of short-chain lipid DLPC, but is enriched at the interface between the fluid and gel domains. At high temperatures, in the fluid phase, BR stays in the mixed lipid phase, and the theoretical data suggest a preference of the protein for the long-chain DSPC molecules at the expense of the short-chain DLPC molecules. The combined results of the experiments and the calculations provide evidence that a molecular sorting principle is active because of hydrophobic matching and that BR exhibits physical lipid selectivity. The results are discussed in the general context of membrane organization and compartmentalization and in terms of nanometer-scale lipid-domain formation.

Bacteriorhodopsins↗
PubMed1997

Small-scale lipid-membrane structure: simulation versus experiment.

Recently, it has become obvious that the conventional picture of the fluid lipid-bilayer component of biological membranes being a fairly structureless 'fluid mosaic' solvent is far from correct. The lipid bilayer displays distinct static and dynamic structural organization on a small scale, for example in terms of differentiated lipid domains, and evidence is accumulating that these structures are of importance for the functioning of biological membranes, including the activity of membrane-bound enzymes and receptors and morphological changes at the cell surface. Insight into the relationship between this small-scale structure and biological functioning holds promise for a more rational approach to modulate function via manipulation of the lipid microenvironment and the lipid/protein interface in particular. Computer simulation has proved to be a useful tool in investigating membrane structure on a small scale-specifically the nanometer scale (1-100 nm), which is in between the molecular scale accessible by various spectroscopic techniques and molecular dynamics calculations, and the micrometer scale accessible by scattering and microscopy techniques.

Computer Simulation↗
PubMed1996

Model of a sub-main transition in phospholipid bilayers.

A recently discovered submain phase transition in multi-lamellar bilayers of long-chain saturated diacyl phosphatidylcholines (Jørgensen, K. (1995) Biochim. Biophys. Acta 1240, 111-114) is discussed in terms of a theoretical molecular interaction model using computer simulation techniques. The model interprets the transition to be due to a decoupling of the acyl-chain melting from the melting of the pseudo-two-dimensional crystalline lattice of the P beta' phase. A two-stage melting process is predicted by the calculations suggesting that the sub-main transition involves a lattice melting whereas the acyl-chain melting takes place at a higher temperature at the main transition. The calculated heat contents of the two transitions as well as the chain-length dependence compare favorably with experimental data for multi-lamellar phosphatidylcholine lipid bilayers.

Calorimetry↗
PubMed1996

Systematic relationship between phospholipase A2 activity and dynamic lipid bilayer microheterogeneity.

A standing hypothesis in membrane biology implies that the collective physical properties of the lipid bilayer component of biological membranes can modulate the activity of membrane-associated proteins. We provide strong support for this hypothesis by exploring a model system, phospholipase A2 catalyzed hydrolysis of one-component phospholipid vesicles. For vesicles of lipids with different chain lengths we observe, as a function of temperature and chain length, a systematic variation of the characteristic lag time for the onset of rapid phospholipase A2 hydrolysis. These results, combined with theoretical results obtained from computer simulation of the gel-to-fluid phase transition in the unhydrolyzed lipid bilayers, enable us to demonstrate a strong correlation between the lag time and the degree of bilayer microheterogeneity in the phase transition region. Insight into the nature of this correlation suggests rational ways of modulating enzyme activity by modifying the physical properties of the lipid bilayer.

Computer Simulation↗
PubMed1996

Lindane suppresses the lipid-bilayer permeability in the main transition region.

The effects of a small molecule, the insecticide lindane, on unilamellar DMPC bilayers in the phase transition region, have been studied by means of differential scanning calorimetry and fluorescence spectroscopy. The calorimetric data show that increasing concentrations of lindane broaden the transition and lower the transition temperature, without changing the transition enthalpy significantly. Lindane therefore enhances the thermal fluctuations of the bilayer. The calorimetric data furthermore suggest that the bilayer structure is intact and not disrupted by even high concentrations (32 mol%) of lindane. Fluorescence spectroscopy was used to measure the passive permeability of unilamellar DMPC bilayers to Co2+ ions. The data show that lindane seals the bilayer for Co2+ penetration and that this effect increases with increasing lindane concentration. The results are discussed in relation to the effects on the permeability of other small molecules, e.g., anesthetics.

Calorimetry, Differential Scanning↗
PubMed1996

Indirect evidence for lipid-domain formation in the transition region of phospholipid bilayers by two-probe fluorescence energy transfer.

The fluorescence energy transfer between two lipid probes, N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-1, 2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine (donor) and N-(Lissamine rhodamine B sulfonyl)-1, 2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine (acceptor), incorporated into 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine unilamellar and multilamellar lipid bilayers, is studied in the temperature region of the main phase transition. The two probes display different relative solubilities in the gel and fluid lipid-bilayer phases. A distinct maximum in the fluorescence intensity of the donor is observed in the transition region, indicating that the two probes are demixing and hence increasing their average separation. The observation is interpreted in terms of dynamic segregation of the two probes into coexisting gel and fluid lipid domains that are formed dynamically in the transition region due to strong density fluctuations. The interpretation of the experimental observations is supported by a detailed theoretical calculation using computer simulation of a microscopic model that takes full account of diffusion of the two probes and the fluctuations of gel and fluid lipid domains characteristic of the main phase transition.

Calorimetry, Differential Scanning↗
PubMed1996

The effect of increasing membrane curvature on the phase transition and mixing behavior of a dimyristoyl-sn-glycero-3-phosphatidylcholine/ distearoyl-sn-glycero-3-phosphatidylcholine lipid mixture as studied by Fourier transform infrared spectroscopy and differential scanning calorimetry.

The phase transition behavior of a lipid bilayer of dimyristoyl-sn-glycero-3-phosphatidylcholine/distearoyl-sn-glycero-3- phosphatidylcholine (DMPC-d54/DSPC) (1:1) on a solid support with varying curvatures was investigated with differential scanning calorimetry, infrared spectroscopy, and model calculations. With increasing curvature the temperatures of the liquidus and solidus points are shifted to lower values by up to 7 degrees C and 15 degrees C, and the mixing of the two lipid species in the two phase region is altered. With increasing curvature the DSPC dominates the gel phase, whereas the DMPC-d54 is expelled to the fluid phase. Whereas the planar system shows a nearly simultaneous phase transition of DSPC and DMPC-d54, the spherical system with the highest curvature exhibits an almost complete separation of the phase transitions of the two lipids. Model calculations suggest that the shift of the liquidus point can be understood as a reduction of the lateral pressure in the bilayer with increasing curvature. The shift of the solidus line is interpreted as a result of the increased demixing of the two components in the two-phase region with increasing curvature due to lowering of the lateral pressure.

Biophysical Phenomena↗
PubMed1995

Calorimetric and theoretical studies of the effects of lindane on lipid bilayers of different acyl chain length.

The effects of the insecticide lindane on the phase transition in multilamellar bilayers of saturated diacylphosphatidylcholines of different acyl chain length (DC14PC, DC16PC, and DC18PC) have been studied by means of differential scanning calorimetry (DSC), as well as computer-simulation calculations on a molecular interaction model. The calorimetric data show that increasing concentrations of lindane lower the transition temperature and lead to a broadening of the specific heat in a systematic way depending on the lipid acyl chain length. Kinetic effects in the observed calorimetric traces indicate that the incorporation of lindane into multilamellar lipid bilayers is slow, but faster for the shorter lipid species. Large unilamellar vesicles do not show such kinetic effects. The transition enthalpy is for all three lipid species found to be independent of the lindane concentration which implies that the entropy of mixing is vanishingly small. This lends support to a microscopic molecular interaction model which assigns the absorbed lindane molecules to interstitial sites in the bilayer. Computer-simulation calculations on this model, which assumes a specific interaction between lindane and certain excited acyl chain configurations, lead to predictions of the lipid-water partition coefficient in qualitative agreement with experimental measurements (Antunes-Madeira and Madeira (1985) Biochim. Biophys. Acta 820, 165-172). The partition coefficient has a peak near the phase transition which is a consequence of enhanced interfacial adsorption of lindane at lipid-domain interfaces.

Calorimetry, Differential Scanning↗
PubMed1995

Phase separation dynamics and lateral organization of two-component lipid membranes.

The non-equilibrium dynamic ordering process of coexisting phases has been studied for two-component lipid bilayers composed of saturated di-acyl phospholipids with different acyl chain lengths, such as DC14PC-DC18PC and DC12PC-DC18PC. By means of a microscopic interaction model and computer-simulation techniques the non-equilibrium properties of these two mixtures have been determined with particular attention paid to the effects of the non-equilibrium ordering process on membrane heterogeneity in terms of local and global lateral membrane organization. The results reveal that a sudden temperature change that takes the lipid mixture from the fluid one-phase region into the gel-fluid phase-coexistence region leads to the formation of a large number of small lipid domains which slowly are growing in time. The growth of the lipid domains, which is limited by long-range diffusion of the lipid molecules within the two-dimensional membrane plane, gives rise to the existence of a highly heterogeneous percolative-like structure with a network of interfacial regions that have properties different from those of the phase-separated gel and fluid bulk phases. The results, which are discussed in relation to recent experimental observations interpreted in terms of a percolative-like membrane structure within the two phase region (Almeida, P.F.F., Vaz, W.L.C., and T.E. Thompson. 1992. Biochemistry 31:7198-7210), suggest that non-equilibrium effects may influence lipid domain formation and membrane organization on various length and time scales. Such effects might be of importance in relation to membrane processes that require molecular mobility of the membrane components in restricted geometrical environments of the compartmentalized lipid membrane.

Computer Simulation↗
PubMed1994

Dynamical order and disorder in lipid bilayers.

Various order and disorder phenomena in lipid bilayers are considered as they arise due to the very many-particle character of the bilayer. Particular attention is paid to dynamically maintained order in terms of lateral density- and compositional fluctuations that lead to dynamic heterogeneity, local structure, and lipid-domain formation on length scales of 10-1000 A. The influence of cholesterol and various drugs on the local structure is described. A discussion is presented of the possible role played by lipid order and disorder phenomena for the functional dynamics of membranes.

Anesthetics↗
PubMed1993

Phase equilibria and local structure in binary lipid bilayers.

A molecular interaction model is used to describe the phase diagram of two-component phospholipid bilayer membranes of saturated phospholipids, DCnPC, with different acyl-chain lengths, n = 12,14,18,20. The interaction between acyl chains of different length is formulated in terms of a hydrophobic mismatch which permits the series of binary phase diagrams to be calculated in terms of a single 'universal' interaction parameter. The properties of the model are calculated by computer-simulation techniques which not only permit determination of the specific-heat function and the phase diagram but also reveal the local structure of the mixture in the different parts of the phase diagram. The local structure is described pictorially and characterized quantitatively in terms of a correlation function. It is shown that the non-ideal mixing of lipid species due to mismatch in the hydrophobic lengths leads to a progressively increasing local ordering as the chain-length difference is increased. A pronounced local structure is found to persist deep inside the fluid phase of the mixture. The local structure is discussed in relation to the features observed in the specific-heat function, for which theoretical data, as well as experimental data obtained from differential-scanning calorimetry are presented.

Computer Simulation↗