Phase Separation in Atomistic Simulations of Model Membranes.

Understanding the lateral organization in plasma membranes remains an open problem despite a large body of research. Model membranes with coexisting micrometer-size domains are routinely employed as simplified models of plasma membranes. Many molecular dynamics simulations have investigated phase separation in model membranes at the coarse-grained level, but atomistic simulations remain computationally challenging.

Cholesterol Flip-Flop in Heterogeneous Membranes.

Cholesterol is the most abundant molecule in the plasma membrane of mammals. Its distribution across the two membrane leaflets is critical for understanding how cells work. Cholesterol trans-bilayer motion (flip-flop) is a key process influencing its distribution in membranes.

Low- q Bicelles Are Mixed Micelles.

Bicelles are used in many membrane protein studies because they are thought to be more bilayer-like than micelles. We investigated the properties of "isotropic" bicelles by small-angle neutron scattering, small-angle X-ray scattering, fluorescence anisotropy, and molecular dynamics. All data suggest that bicelles with a q value below 1 deviate from the classic bicelle that contains lipids in the core and detergent in the rim.

Composition Fluctuations in Lipid Bilayers.

Cell membranes contain multiple lipid and protein components having heterogeneous in-plane (lateral) distribution. Nanoscale rafts are believed to play an important functional role, but their phase state-domains of coexisting phases or composition fluctuations-is unknown. As a step toward understanding lateral organization of cell membranes, we investigate the difference between nanoscale domains of coexisting phases and composition fluctuations in lipid bilayers.

Computer simulations of lung surfactant.

Lung surfactant lines the gas-exchange interface in the lungs and reduces the surface tension, which is necessary for breathing. Lung surfactant consists mainly of lipids with a small amount of proteins and forms a monolayer at the air-water interface connected to bilayer reservoirs. Lung surfactant function involves transfer of material between the monolayer and bilayers during the breathing cycle.

Density based visualization for molecular simulation.

Molecular visualization of structural information obtained from computer simulations is an important part of research work flow. A good visualization technique should be capable of eliminating redundant information and highlight important effects clarifying the key phenomena in the system. Current methods of presenting structural data are mostly limited to variants of the traditional ball-and-stick representation.

Computer simulations of phase separation in lipid bilayers and monolayers.

Studying phase coexistence in lipid bilayers and monolayers is important for understanding lipid-lipid interactions underlying lateral organization in biological membranes. Computer simulations follow experimental approaches and use model lipid mixtures of simplified composition. Atomistic simulations give detailed information on the specificity of intermolecular interactions, while coarse-grained simulations achieve large time and length scales and provide a bridge towards state-of-the-art experimental techniques.

The mechanism of collapse of heterogeneous lipid monolayers.

Collapse of homogeneous lipid monolayers is known to proceed via wrinkling/buckling, followed by folding into bilayers in water. For heterogeneous monolayers with phase coexistence, the mechanism of collapse remains unclear. Here, we investigated collapse of lipid monolayers with coexisting liquid-liquid and liquid-solid domains using molecular dynamics simulations.

Interaction of pristine and functionalized carbon nanotubes with lipid membranes.

Carbon nanotubes are widely used in a growing number of applications. Their interactions with biological materials, cell membranes in particular, is of interest in applications including drug delivery and for understanding the toxicity of carbon nanotubes. We use extensive molecular dynamics simulations with the MARTINI model to study the interactions of model nanotubes of different thickness, length, and patterns of chemical modification with model membranes.

Computer simulations of the phase separation in model membranes.

We used computer simulations to investigate the properties of model lipid membranes with coexisting phases. This is relevant for understanding lipid-lipid interactions underlying lateral organization in biological membranes. Molecular dynamics simulations with the MARTINI coarse-grained force field were employed to study lipid bilayers -40 nm in lateral dimension on a 20 micros time scale.

Simulations of lipid monolayers.

A lipid monolayer lining a boundary between two immiscible phases forms a complex interface with inhomogeneous distribution of forces. Unlike lipid bilayers, monolayers are formed in asymmetric environment and their properties depend strongly on lipid surface density. The monolayer properties are also affected significantly by the representation of the pure interface.

Molecular view of phase coexistence in lipid monolayers.

We used computer simulations to study the effect of phase separation on the properties of lipid monolayers. This is important for understanding the lipid-lipid interactions underlying lateral heterogeneity (rafts) in biological membranes and the role of domains in the regulation of surface tension by lung surfactant. Molecular dynamics simulations with the coarse-grained MARTINI force field were employed to model large length (~80 nm in lateral dimension) and time (tens of microseconds) scales.

Lipid Nanoparticles Containing siRNA Synthesized by Microfluidic Mixing Exhibit an Electron-Dense Nanostructured Core.

Lipid nanoparticles (LNP) containing ionizable cationic lipids are the leading systems for enabling therapeutic applications of siRNA; however, the structure of these systems has not been defined. Here we examine the structure of LNP siRNA systems containing DLinKC2-DMA(an ionizable cationic lipid), phospholipid, cholesterol and a polyethylene glycol (PEG) lipid formed using a rapid microfluidic mixing process. Techniques employed include cryo-transmission electron microscopy, (31)P NMR, membrane fusion assays, density measurements, and molecular modeling.

Molecular structure of membrane tethers.

Membrane tethers are nanotubes formed by a lipid bilayer. They play important functional roles in cell biology and provide an experimental window on lipid properties. Tethers have been studied extensively in experiments and described by theoretical models, but their molecular structure remains unknown due to their small diameters and dynamic nature.

Lung surfactant protein SP-B promotes formation of bilayer reservoirs from monolayer and lipid transfer between the interface and subphase.

We investigated the possible role of SP-B proteins in the function of lung surfactant. To this end, lipid monolayers at the air/water interface, bilayers in water, and transformations between them in the presence of SP-B were simulated. The proteins attached bilayers to monolayers, providing close proximity of the reservoirs with the interface.

Direct simulation of protein-mediated vesicle fusion: lung surfactant protein B.

We simulated spontaneous fusion of small unilamellar vesicles mediated by lung surfactant protein B (SP-B) using the MARTINI force field. An SP-B monomer triggers fusion events by anchoring two vesicles and facilitating the formation of a lipid bridge between the proximal leaflets. Once a lipid bridge is formed, fusion proceeds via a previously described stalk - hemifusion diaphragm - pore-opening pathway.

Lateral pressure profiles in lipid monolayers.

We have used molecular dynamics simulations with coarse-grained and atomistic models to study the lateral pressure profiles in lipid monolayers. We first consider simple oillair and oil/water interfaces, and then proceed to lipid monolayers at air/water and oil/water interfaces. The results are qualitatively similar in both atomistic and coarse-grained models.

Molecular dynamics study of the effect of cholesterol on the properties of lipid monolayers at low surface tensions.

We have investigated the effect of cholesterol concentration on the properties of lipid monolayers at air/water interfaces at low surface tensions. This is of interest for understanding the properties and function of lung surfactant monolayers. Lung surfactant lines the gas exchange interface in the lungs and dramatically reduces the surface tension, thereby preventing lung collapse and decreasing the work associated with breathing.

The molecular mechanism of lipid monolayer collapse.

Lipid monolayers at an air-water interface can be compressed laterally and reach high surface density. Beyond a certain threshold, they become unstable and collapse. Lipid monolayer collapse plays an important role in the regulation of surface tension at the air-liquid interface in the lungs.

Computer simulation study of fullerene translocation through lipid membranes.

Recent toxicology studies suggest that nanosized aggregates of fullerene molecules can enter cells and alter their functions, and also cross the blood-brain barrier. However, the mechanisms by which fullerenes penetrate and disrupt cell membranes are still poorly understood. Here we use computer simulations to explore the translocation of fullerene clusters through a model lipid membrane and the effect of high fullerene concentrations on membrane properties.

Pressure-area isotherm of a lipid monolayer from molecular dynamics simulations.

We calculated the pressure-area isotherm of a dipalmitoyl-phosphatidylcholine (DPPC) lipid monolayer from molecular dynamics simulations using a coarse-grained molecular model. We characterized the monolayer structure, geometry, and phases directly from the simulations and compared the calculated isotherm to experiments. The calculated isotherm shows liquid-expanded and liquid-condensed phases and their coexistence plateau.

The molecular mechanism of monolayer-bilayer transformations of lung surfactant from molecular dynamics simulations.

The aqueous lining of the lung surface exposed to the air is covered by lung surfactant, a film consisting of lipid and protein components. The main function of lung surfactant is to reduce the surface tension of the air-water interface to the low values necessary for breathing. This function requires the exchange of material between the lipid monolayer at the interface and lipid reservoirs under dynamic compression and expansion of the interface during the breathing cycle.

An elevated level of cholesterol impairs self-assembly of pulmonary surfactant into a functional film.

In adult respiratory distress syndrome, the primary function of pulmonary surfactant to strongly reduce the surface tension of the air-alveolar interface is impaired, resulting in diminished lung compliance, a decreased lung volume, and severe hypoxemia. Dysfunction coincides with an increased level of cholesterol in surfactant which on its own or together with other factors causes surfactant failure. In the current study, we investigated by atomic force microscopy and Kelvin-probe force microscopy how the increased level of cholesterol disrupts the assembly of an efficient film.

Analytical derivation of thermodynamic characteristics of lipid bilayer from a flexible string model.

We introduce a flexible string model of the hydrocarbon chain and derive an analytical expression for the lateral pressure profile across the hydrophobic core of the membrane. The pressure profile influences the functioning of the embedded proteins and is difficult to measure experimentally. In our model the hydrocarbon chain is represented as a flexible string of finite thickness with a given bending rigidity.