Membrane disordering induced by chloroform and carbon tetrachloride

We studied effects of chloroform and carbon tetrachloride on bilayer membranes of dimyristoyl-phosphatidylcholine (DMPC) and egg yolk phosphatidylcholine (Egg-PC) by birefringence, dynamic light scattering and fluorescence methods. It is shown that interference light due to the membrane birefringence considerably decreases by addition of the organohalogen compounds for both lipid membranes, indicating a significant decrease in membrane order. In addition, results of dynamic light scattering and turbidity measurements show a rupture of multilamellar DMPC vesicles induced by addition of chloroform at concentrations above 0.2 v/v%. No rupture of the vesicles is observed within the limit of solubility of carbon tetrachloride in water, but excessive addition of carbon tetrachloride (above 0.2 v/v%) induces the vesicle rupture. Chain orientational order was estimated from the interference light intensity at low concentrations of the organohalogen compounds without the occurrence of the vesicle rupture. The estimation shows a monotonic decrease in the chain order with increasing the concentration. The decreases in DMPC chain order by chloroform and by carbon tetrachloride are about 17% at 0.2 v/v% and 23% at 0.05 v/v%, respectively. The reduction in the chain order is correlated with an increase in the membrane fluidity observed by excimer fluorescence of pyrene incorporated to the membrane. Behavior of membrane disordering of Egg-PC is approximately similar with that of DMPC. This implies the strong interaction between the organohalogen compounds and the lipid chains, whether or not the bilayer has the vacancy resulted from unsaturated double bonds and different chains in length. The results of this work suggest that damages of biological membranes by chloroform and tetrachloride are not only induced by a direct attack on proteins but also by a significant membrane disorder.     

Voltammetric study of gold-supported lipid membranes in the presence of perfluorooctanesulphonic acid

The effect of perfluorooctanesulphonic acid (PFOS) on lipid membranes was studied using supported 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) bilayer as the model membrane. Phospholipid bilayer was deposited on gold electrode using a combination of the Langmuir–Blodgett and Langmuir–Schaefer (LB/LS) techniques. Electrodes were modified with two different types of membranes: DMPC bilayers initially containing PFOS and pure DMPC bilayers later exposed to the PFOS solutions. Such approach allowed studying both the changes in membrane characteristic imposed by the perfluorinated compound present in the model membrane and the process of its incorporation into the membrane. Studies with anticancer drug doxorubicin revealed that PFOS inhibits drug transport through the phospholipid bilayer and its effect can be compared to that of cholesterol. Moreover, the different trends observed in the changes in electron transfer rate constant (k_s) calculated for ferricyanides and in peak current of hexaamineruthenium chloride showed that electrostatic interactions between electroactive probes and PFOS molecules incorporating into phospholipid bilayers play an important role and should be taken into account while explaining the interactions of perfluorooctanesulphonic acid with model biological membranes.     

The cell-penetrating peptide TAT(48-60) induces a non-lamellar phase in DMPC membranes.

Cell-penetrating peptides (CPPs) are short polycationic sequences that can translocate into cells without disintegrating the plasma membrane. CPPs are useful tools for delivering cargo, but their molecular mechanism of crossing the lipid bilayer remains unclear. Here we study the interaction of the HIV-derived CPP TAT (48-60) with model membranes by solid-state NMR spectroscopy and electron microscopy. The peptide induces a pronounced isotropic (31)P NMR signal in zwitterionic DMPC, but not in anionic DMPG bilayers. Octaarginine and to a lesser extent octalysine have the same effect, in contrast to other cationic amphiphilic membrane-active peptides. The observed non-lamellar lipid morphology is attributed to specific interactions of polycationic peptides with phosphocholine head groups, rather than to electrostatic interactions. Freeze-fracture electron microscopy indicates that TAT(48-60) induces the formation of rodlike, presumably inverted micelles in DMPC, which may represent intermediates during the translocation across eukaryotic membranes.     

Impact on lipid membrane organization by free branched-chain fatty acids

Here, we exploit the non-invasive techniques of solid-state NMR (nuclear magnetic resonance) and differential scanning calorimetry (DSC) to study the effect of free iso and ante-iso branched chain fatty acids (BCFAs) on the physicochemical properties of lipid membranes. Free fatty acids are present in biological membranes at low abundance, but can influence the cellular function by modulating the membrane organization. Solid state NMR spectra of dimyristoylphosphatidylcholine (DMPC) lipid membranes containing either free 12-methyltetradecanoic acid (a15:0) or free 13-methyltetradecanoic acid (i15:0), show significant differences in their impact on the lipid bilayer. Chain order profiles obtained by deuterium NMR on fully deuterated DMPC-d(67) bilayers revealed an ordering effect induced by both fatty acids on the hydrophobic membrane core. This behavior was also visible in the corresponding DSC thermograms where the main phase transition of DMPC bilayers-indicative of the hydrophobic membrane region-was shifted to higher temperatures, with the iso isomer triggering more pronounced changes as compared to the ante-iso isomer. This is probably due to a higher packing density in the core of the lipid bilayer, which causes reduced diffusion across membranes. By utilizing the naturally occurring spin reporters nitrogen-14 and phosphorus-31 present in the hydrophilic DMPC headgroup region, even fatty acid induced changes at the membrane interface could be detected, an observation reflecting changes in the lipid headgroup dynamics.     

Influence of perfluorinated compounds on the properties of model lipid membranes

The influence of selected perfluorinated compounds (PFCs), perfluorooctanoic acid (PFOA) or perfluorooctanesulfonic acid (PFOS), on the structure and organization of lipid membranes was investigated using model membranes-lipid monolayers and bilayers. The simplest model--a lipid monolayer--was studied at the air-water interface using the Langmuir-Blodgett technique with surface pressure and surface potential measurements. Lipid bilayers were characterized by NMR techniques and molecular dynamics simulations. Two phospholipids, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), characterized by different surface properties have been chosen as components of the model membranes. For a DPPC monolayer, a phase transition from the liquid-expanded state to the liquid-condensed state can be observed upon compression at room temperature, while a DMPC monolayer under the same conditions remains in the liquid-expanded state. For each of the two lipids, the presence of both PFOA and PFOS leads to the formation of a more fluidic layer at the air-water interface. Pulsed field gradient NMR measurements of the lateral diffusion coefficient (DL) of DMPC and PFOA in oriented bilayers reveal that, upon addition of PFOA to DMPC bilayers, DL of DMPC decreases for small amounts of PFOA, while larger additions produce an increased DL. The DL values of PFOA were found to be slightly larger than those for DMPC, probably as a consequence of the water solubility of PFOA. Furthermore, 31P and 2H NMR showed that the gel-liquid crystalline phase transition temperature decreased by the addition of PFOA for concentrations of 5 mol % and above, indicating a destabilizing effect of PFOA on the membranes. Deuterium order parameters of deuterated DMPC were found to increase slightly upon increasing the PFOA concentration. The monolayer experiments reveal that PFOS also penetrates slowly into already preformed lipid layers, leading to a change of their properties with time. These experimental observations are in qualitative agreement with the computational results obtained from the molecular dynamics simulations showing a slow migration of PFCs from the surrounding water phase into DPPC and DMPC bilayers.     

Probing the molecular-scale lipid bilayer response to shear flow using nonequilibrium molecular dynamics

A nonequilibrium molecular dynamics simulation of the response of dimyristoylphosphatidylcholine (DMPC) bilayers to a solvent shear flow is presented. Application of shear flow to planar, stationary DMPC bilayers results in a redistribution of the membrane density profile along the bilayer normal due to the alignment of the lipids in the direction of flow and an increase in average lipid chain length. An increase in the intermolecular and intramolecular order of the lipids in response to the shear flow is also observed. This study provides groundwork for understanding the mechanism of the full response of lipid bilayers to externally imposed solvent shear flows, beginning with the response in the absence of collective lipid motions such as undulations and bilayer flow.     

Losartan's affinity to fluid bilayers modulates lipid-cholesterol interactions

Losartan is an angiotensin II receptor antagonist mainly used for the regulation of high blood pressure. Since it was anticipated that losartan reaches the receptor site via membrane diffusion, the impact of losartan on model membranes has been investigated by small angle X-ray scattering. For this purpose 2-20 mol% losartan was incorporated into dimyristoyl-phosphatidylcholine (DMPC) and palmitoyl-oleoyl-phosphatidylcholine (POPC) bilayers and into their binary mixtures with cholesterol in the concentration range of 0 to 40 mol%. Effects of losartan on single component bilayers are alike. Partitioning of losartan into the membranes confers a negative charge to the lipid bilayers that causes the formation of unilamellar vesicles and a reduction of the bilayer thickness by 3-4%. Analysis of the structural data resulted in an estimate for the partial area of losartan, A(Los) ≈ 40 ?(2). In the presence of cholesterol, differences between the effects of losartan on POPC and DMPC are striking. Membrane condensation by cholesterol is retarded by losartan in POPC. This contrasts with DMPC, where an increase of the cholesterol content shifts the partitioning equilibrium of losartan towards the aqueous phase, such that losartan gets depleted from the bilayers from 20 mol% cholesterol onwards. This indicates (i) a chain-saturation dependent competition of losartan with lipid-cholesterol interactions, and (ii) the insolubility of losartan in the liquid ordered phase of PCs. Consequently, losartan's action is more likely to take place in fluid plasma membrane patches rather than in domains rich in cholesterol and saturated lipid species such as in membrane rafts.     

Determination of the line tension of giant vesicles from pore-closing dynamics

Giant vesicles generated from synthetic and natural lipids such as phosphatidylcholines are useful models for understanding mechanical properties of cell membranes. Line tension is the one-dimensional force enabling the closing of transient pores on cell membranes. Transient pores were repeatedly and reproducibly formed on the membrane edge of giant vesicles generated from synthetic and natural phosphatidylcholines employing a nitrogen-pumped coumarin dye laser (440 nm). Line tension was determined at room temperature from closing of these pores that occurred over several seconds when the radius of the vesicle could be considered to be constant. The value of line tension depends on the nature of the lipid for single lipid systems, which, at room temperature, yielded a vesicle bilayer region in the gel, fluid, or mixed gel and fluid phases. The line tension for vesicles generated from phosphatidylcholines with saturated acyl chains of lengths of 12-18 carbon atoms ranges from 1 to 12 pN, exhibiting an increase with chain length. Vesicles generated from the natural Egg-PC, which is a mixture of lipids, are devoid of phase transition and exhibited the largest value of line tension (32 pN). This value is much larger than that estimated from the line tensions of vesicles obtained from lipids with homologous acyl chains. This study, to our knowledge, is the first to employ laser ablation to generate transient pores and determine line tension from the rate of pore closure and demonstrate a relationship between line tension and acyl chain length.     

Phospholipids Bilayers as Molecular Models for Drug- Membrane Interactions. The Case of the Antiepileptics Phenytoin and Carbamazepine

With the aim to better understand the molecular mechanisms of the interaction of phenytoin and carbamazepine with cell membranes we utilized a well-established model consisting in intact human erythrocytes, isolated unsealed human erythrocyte membranes (IUM) and molecular models of its membrane. The latter consisted of bilayers of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidyl-ethanolamine (DMPE), representative of phospholipid classes respectively located in the outer and inner monolayers of erythrocytes and other cell membranes. This report presents the following evidence that phenytoin and carbamazepine interact with membrane phospholipids: a) X-ray diffraction and fluorescence spectroscopy showed that both drugs preferentially interacted with DMPC; b) in IUM, the drugs induced a disordering effect on the polar head groups and acyl chains of the eryhrocyte membrane lipid bilayers; c) electron microscopy observations of human erythrocytes showed the echinocyte formation, an effect due to phenytoin and carbamazepine insertion in the outer monolayer of the red cell membrane.     

Evidence for the hydration effect at the semiconductor phospholipid-bilayer interface by TiO2 photocatalysis

The interactions of TiO2 with phospholipid bilayers found in cell membrane walls were observed to perturb the bilayer structure under UVA light irradiation. The structure changes in the phospholipid bilayers upon contact with TiO2 under light and in the dark were followed by X-ray diffraction. Hydration effects at the semiconductor-phospholipid interface played an important role in the degradation of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE) bilayers taken as cell wall lipid bilayer models. Evidence is provided that the fluidity of the phospholipid bilayers plays a significant role when interacting in the dark with the TiO2 or in processes mediated by TiO2 under light irradiation.     

Interactions of membrane-active peptides with thick, neutral, nonzwitterionic bilayers

Alamethicin is a well-studied channel-forming peptide that has a prototypical amphipathic helix structure. It permeabilizes both microbial and mammalian cell membranes, causing loss of membrane polarization and leakage of endogenous contents. Antimicrobial peptide-lipid systems have been studied quite extensively and have led to significant advancements in membrane biophysics. These studies have been performed on lipid bilayers that are generally charged or zwitterionic and restricted to a thickness range of 3-5 nm. Bilayers of amphiphilic diblock copolymers are a relatively new class of membranes that can have significantly different physicochemical properties compared with those of lipid membranes. In particular, they can be made uncharged, nonzwitterionic, and much thicker than their lipid counterparts. In an effort to extend studies of membrane-protein interactions to these synthetic membranes, we have characterized the interactions of alamethicin and several other membrane-active peptides with diblock copolymer bilayers. We find that although alamethicin is too small to span the bilayer, the peptide interacts with, and ruptures, thick polymer membranes.     

Effect of polymer characteristics on structure of polymer-liposome complexes

In the current study, we examined the effect of polymer characteristics on the structure of complexes formed between poly(methacrylic acid-co-n-alkyl methacrylate) and with phosphatidylcholine/cholesterol liposomes. We varied the polymer concentration in the vesicles, the preparation concentration of lipid and polymer components during preparation, the molecular weight of the polymer chain, the molecular weight of the polymer's hydrophobic side groups and their mole fraction. The vesicle behavior indicated polymer-free bilayers and bilayers complexed with polymer coexisted at low polymer concentrations. As the polymer concentration exceeds a critical level, however, the system became homogeneous, indicating bilayer uniformity of the bilayer. As the polymer content was raised, the vesicle size and fluidity increased, and the transition temperature decreased. We found that the vesicle size mostly affects the membrane fluidity. We also found that the thermal properties (transition temperature and the magnitude of heat capacity of the peak, DeltaCp) are governed by the effects of the polymer on the structure of bilayer. The length of the alkyl chain of the polymer is shown to significantly affect the structure of polymer-liposome complexes, as did the chain molecular weight and mole concentration of hydrophobic group in the polymer.     

Nonuniform lipid distribution in membranes

The noniform lateral and transbilayer lipid arrangement existing in two-component lipid bilayers are reviewed.

The lateral lipid organization is considered on the basis of the temperature-composition phase diagrams of the lipid binaries. A comparative analysis of the phase diagrams of synthetic phospholipid mixtures is carried out. The various types of the phase diagrams observed are set in a continuous row determined by the increase of the lipid lateral immiscibility. A special emphasis is laid on the appearance of peculiar points in the phase diagrams--triple, critical, and isoconcentration points. Two basic statistical-mechanical methods for simulation of phase diagrams--Bragg-Williams (regular solutions, mean field) and quasichemical--are compared. Stability criteria indicating the regions of lateral phase separation are also given. The main advantage of the quasichemical method is that it also allows the short-range order in the lipid arrangement to be determined.

The physical interactions contributing to an equilibrium lipid asymmetry in mixed lipid bilayers are pointed out. The most important among them are: (i) electrostatic forces induced by differences in the membrane electric double layers; (ii) nonideal lateral mixing of the lipids; (iii) packing restrictions important in curved bilayers.

A unified electrostatic model is presented to calculate the surface charge asymmetry created by any factors affecting the electric double layers of the bilayer (external electric potential, overlapping electric double layers in parallel membranes or in vescicles, etc.).

The transmembrane asymmetry strongly depends on the degree of c corrections may increase up two-three times the asymmetry induced by factors of the order of 1–3 kT. A typical nonideality effect, which may be used in an experimental verification, is the appearance of an extremum in the dependence of the asymmetry on the mole fraction of the components.

As previously shown in other reviews on membrane organization, the packing restrictions are of importance in highly curved bilayers, e.g., in small unilamellar vesicles.

The experimental data on the asymmetry of two-component small unilamellar vesicles are summarized and some general conclusions are formulated.

With a view toward the native membranes, some inferences are drawn about (i) the state of thermodynamic equilibrium and (ii) the lipid organization in multicomponent membranes.     

Cholesterol modulates amiodarone-membrane interactions in model and native membranes

The effects of cholesterol, a lipid mostly found in the sarcolemmal membranes, on the interaction of amiodarone with synthetic models of dimyristoylphosphatidylcholine (DMPC) and with native models of mitochondria and brain microsomes was studied. Alterations on the structural order of lipids were assessed by fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene (DPH) probing the bilayer core, and of the propionic acid derivative 3-(p-(6-phenyl)-1,3,5-hexatrienyl)phenylpropionic acid (DPH-PA) probing the outer regions of the bilayer. As detected by the probes and according to classic observations, cholesterol progressively increased the molecular order in the fluid phase of DMPC. Additionally, it modulated the type and extension of amiodarone effects. For low cholesterol concentrations (≤10–15 mol%), amiodarone (50 μM) ordered DMPC bilayers and the effects were almost identical to those observed in pure DMPC. For higher cholesterol concentrations, amiodarone ordering effects decreased slightly and faded for cholesterol concentrations as high as 25 and 30 mol%, when detected by DPH-PA and DPH, respectively. Above these high cholesterol concentrations, a crossover from ordering to disordering effects of amiodarone was apparent, either in the upper region of the bilayer or the hydrophobic core. The effects of amiodarone in native membranes of mitochondria and brain microsomes, in which "native" cholesterol accounts for about 0 and 25 mol%, respectively, correlated reasonably with the results in models of synthetic lipids. There is a close relationship between cholesterol concentration and amiodarone effects, in either synthetic models or native model membranes. Therefore, it may be predicted that the lipid physicochemical properties regulated by cholesterol concentration will also modulate the effects of amiodarone in sarcolemma.     

Computational analysis of local membrane properties

In the field of biomolecular simulations, dynamics of phospholipid membranes is of special interest. A number of proteins, including channels, transporters, receptors and short peptides are embedded in lipid bilayers and tightly interact with phospholipids. While the experimental measurements report on the spatial and/or temporal average membrane properties, simulation results are not restricted to the average properties. In the current study, we present a collection of methods for an efficient local membrane property calculation, comprising bilayer thickness, area per lipid, deuterium order parameters, Gaussian and mean curvature. The local membrane property calculation allows for a direct mapping of the membrane features, which subsequently can be used for further analysis and visualization of the processes of interest. The main features of the described methods are highlighted in a number of membrane systems, namely: a pure dimyristoyl-phosphatidyl-choline (DMPC) bilayer, a fusion peptide interacting with a membrane, voltage-dependent anion channel protein embedded in a DMPC bilayer, cholesterol enriched bilayer and a coarse grained simulation of a curved palmitoyl-oleoyl-phosphatidyl-choline lipid membrane. The local membrane property analysis proves to provide an intuitive and detailed view on the observables that are otherwise interpreted as averaged bilayer properties.     

大分子拥挤环境中脂肪酸影响磷脂囊泡相变的差示扫描量热研究

脂肪酸诱导的磷脂膜的热力学行为对于认识细胞内复杂的机制有着重要意义,而前人在研究脂肪酸与磷脂膜相互作用时大都在稀溶液中进行;拥挤环境下脂肪酸诱导磷脂膜的相变行为还未见报道。本文以二肉豆蔻酰磷脂酰胆碱(DMPC)构建囊泡模型,采用差示扫描量热法系统地研究了在不同浓度、不同分子量的聚乙二醇(PEG)拥挤环境中不同结构的脂肪酸对DMPC磷脂囊泡相变的影响。研究结果表明,在拥挤环境中,PEG对纯的磷脂囊泡相变的影响与大分子的分子量和浓度相关。对于脂肪酸/磷脂囊泡(FA/DMPC),PEG的存在对囊泡相变产生显著影响。在所考察的分子量和浓度范围内,PEG使FA/DMPC囊泡相变增加。短链饱和脂肪酸、不饱和脂肪酸原本使DPMC囊泡相变降低,但PEG缩小了降低幅度,甚至导致相变增加。进一步的研究表明,在大多数情况下,PEG对FA/DMPC的相变具有协作增强效应,且其影响均与大分子的分子量和浓度相关。另外,随着PEG浓度的升高,磷脂囊泡的协同单位数逐渐降低,表明拥挤环境会影响磷脂双分子层的均一性,使协同发生相变的分子数降低。本文的研究表明,大分子拥挤环境能够对扰动的磷脂双分子层起到一定的修复作用,这一现象在生物膜相关领域不可忽视。     

A molecular-dynamics study of lipid bilayers: effects of the hydrocarbon chain length on permeability

In this paper, we investigate the effects of the hydrocarbon chain length of lipid molecules on the permeation process of small molecules through lipid bilayers. We perform molecular-dynamics simulations using three kinds of lipid molecules with different chain length: dilauroylphosphatidylcholine, dimyristoylphosphatidylcholine, and dipalmiltoylphosphatidylcholine. Free-energy profiles of O2, CO, NO, and water molecules are calculated by means of the cavity insertion Widom method and the probability ratio method. We show that the lipid membrane with longer chains has a larger and wider energy barrier. The local diffusion coefficients of water across the bilayers are also calculated by the force autocorrelation function method and the velocity autocorrelation function method. The local diffusion coefficients in the bilayers are not altered significantly by the chain length. We estimate the permeability coefficients of water across the three membranes according to the solubility-diffusion model; we find that the water permeability decreases modestly with increasing chain length of the lipid molecules.     

Structure and dynamics of phospholipid bilayers using recently developed general all-atom force fields

Two fully hydrated pure-species phospholipids bilayers, 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-dioleoyl-sn-glycero-3-phosphorylcholine (DOPC), in the fluid phase and explicit solvent have been studied using molecular dynamics simulation. Atom interactions were modeled using recently developed force fields based on AMBER with full atomistic details. Several representative liquid phase properties for the structure and dynamics of lipids with different length of hydrocarbon chains and different level of saturation have been reproduced without artificially biasing the system in order to match experimental data. In particular, as the new GAFF (General Amber Force Field) has not been explicitly developed to reproduce lipid characteristics and is naturally compatible with standard AMBER nucleic acids and proteins parameters, it is here proven a promising tool to study mixed lipid-protein processes as protein activity dependence on membrane composition, permeation of solute across membranes, and other cellular processes.     

Synthesis of lipidated green fluorescent protein and its incorporation in supported lipid bilayers

Herein we report a semisynthetic method of producing membrane-anchored proteins. Ligation of synthetic lipids with designed anchor structures to proteins was performed using native chemical ligation (NCL) of a C-terminal peptide thioester and an N-terminal cysteine lipid. This strategy mimics the natural glycosylphosphatidylinositol (GPI) linkage found in many natural membrane-associated proteins; however, the synthetic method utilizes simple lipid anchors without glycans. Synthetically lipidated recombinant green fluorescent protein (GFP) was shown to be stably anchored to the membrane, and its lateral fluidity was quantitatively characterized by direct fluorescence imaging in supported membranes. Circumventing the steps of purification from native cell membranes, this methodology facilitates the reconstitution of membrane-associated proteins.     

Lipid bilayer disruption by polycationic polymers: the roles of size and chemical functional group

Polycationic polymers are used extensively in biology to disrupt cell membranes and thus enhance the transport of materials into the cell. The highly polydisperse nature of many of these materials makes obtaining a mechanistic understanding of the disruption processes difficult. To design an effective mechanistic study, a monodisperse class of polycationic polymers, poly(amidoamine) (PAMAM) dendrimers, has been studied in the context of supported dimyristoylphosphatidylcholine (DMPC) lipid bilayers using atomic force microscopy (AFM). Aqueous solutions of amine-terminated generation 7 (G7) PAMAM dendrimers caused the formation of 15-40-nm-diameter holes in lipid bilayers. This effect was significantly reduced for smaller G5 dendrimers. For G3, no hole formation was observed. In addition to dendrimer size, surface chemistry had a strong influence on dendrimer-lipid bilayer interactions. In particular, acetamide-terminated G5 did not cause hole formation in bilayers. In all instances, the edges of bilayer defects proved to be points of highest dendrimer activity. A proposed mechanism for the removal of lipids by dendrimers involves the formation of dendrimer-filled lipid vesicles. By considering the thermodynamics, interaction free energy, and geometry of these self-assembled vesicles, a model that explains the influence of polymer particle size and surface chemistry on the interactions with lipid membranes was developed. These results are of general significance for understanding the physical and chemical properties of polycationic polymer interactions with membranes that lead to the transport of materials across cell membranes.