Molecular dynamics simulations of DPPC/CTAB monolayers at the air/water interface.

An atomistic-level understanding of cationic lipid monolayers is essential for development of gene delivery agents based on cationic micelle-like structures. We employ molecular dynamics (MD) simulations for a detailed atomistic study of lipid monolayers composed of both pure zwitterionic dipalmitoylphosphatidylcholine (DPPC) and a mixture of DPPC and cationic cetyltrimethylammonium bromide (CTAB) at the air/water interface. We aim to investigate how the composition of the DPPC/CTAB monolayers affects their structural and electrostatic properties in the liquid-expanded phase. By varying the molar fraction of CTAB, we found the cationic CTAB lipids have significant condensing effect on the DPPC/CTAB monolayers, i.e., at the same surface tension or surface pressure, monolayers with higher CTAB molar fraction have smaller area per lipid. The DPPC/CTAB monolayers are also able to achieve negative surface tension without introducing buckling into the monolayer structure. We also found the condensing effect is caused by the interplay between the cationic CTAB headgroups and the zwitterionic phosphatidylcholine (PC) headgroups which has electrostatic origin. With CTAB in its vicinity, the P-N vector of PC headgroups reorients from being parallel to the monolayer plane to a more vertical orientation. Moreover, detailed analysis of the structural properties of the monolayers, such as the density profile analysis, hydrogen bonding analysis, chain order parameter calculations, and radial distribution function calculations were also performed for better understanding of cationic DPPC/CTAB monolayers.

Porphyrin-phospholipid liposomes permeabilized by near-infrared light.

The delivery of therapeutic compounds to target tissues is a central challenge in treating disease. Externally controlled drug release systems hold potential to selectively enhance localized delivery. Here we describe liposomes doped with porphyrin-phospholipid that are permeabilized directly by near-infrared light. Molecular dynamics simulations identified a novel light-absorbing monomer esterified from clinically approved components predicted and experimentally demonstrated to give rise to a more stable porphyrin bilayer. Light-induced membrane permeabilization is enabled with liposomal inclusion of 10 molar % porphyrin-phospholipid and occurs in the absence of bulk or nanoscale heating. Liposomes reseal following laser exposure and permeability is modulated by varying porphyrin-phospholipid doping, irradiation intensity or irradiation duration. Porphyrin-phospholipid liposomes demonstrate spatial control of release of entrapped gentamicin and temporal control of release of entrapped fluorophores following intratumoral injection. Following systemic administration, laser irradiation enhances deposition of actively loaded doxorubicin in mouse xenografts, enabling an effective single-treatment antitumour therapy.

Melatonin directly interacts with cholesterol and alleviates cholesterol effects in dipalmitoylphosphatidylcholine monolayers.

Melatonin is a pineal hormone that has been shown to have protective effects in several diseases that are associated with cholesterol dysregulation, including cardiovascular disease, Alzheimer's disease, and certain types of cancers. Cholesterol is a major membrane constituent with both a structural and functional influence. It is also known that melatonin readily partitions into cellular membranes. We investigated the effects of melatonin and cholesterol on the structure and physical properties of a 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) monolayer as a simple membrane model using the Langmuir-Blodgett (L-B) monolayer technique and molecular dynamics (MD) simulations. We report that melatonin increases the area per lipid and elastic compressibility of the DPPC monolayer in a concentration dependent manner, while cholesterol has the opposite effect. When both melatonin and cholesterol were present in the monolayer, the compression isotherms showed normalization of the area per molecule towards that of the pure DPPC monolayer, thus indicating that melatonin counteracts and alleviates cholesterol's effects. Atomistic MD simulations of melatonin enriched DPPC systems correlate with our experimental findings and illustrate the structural effects of both cholesterol and melatonin. Our results suggest that melatonin is able to lessen the influence of cholesterol through two different mechanisms. Firstly, we have shown that melatonin has a fluidizing effect on monolayers comprising only lipid molecules. Secondly, we also observe that melatonin interacts directly with cholesterol. Our findings suggest a direct nonspecific interaction of melatonin may be a mechanism involved in reducing cholesterol associated membrane effects, thus suggesting the existence of a new mechanism of melatonin's action. This may have important biological relevance in addition to the well-known anti-oxidative and receptor binding effects.

Bilayer structure and lipid dynamics in a model stratum corneum with oleic acid.

The stratum corneum is the uppermost layer of the skin and acts as a barrier to keep out contaminants and retain moisture. Understanding the molecular structure and behavior of this layer will provide guidance for optimizing its biological function. In this study we use a model mixture comprised of equimolar portions of ceramide NS (24:0), lignoceric acid, and cholesterol to model the effect of the addition of small amounts of oleic acid to the bilayer at 300 and 340 K. Five systems at each temperature have been simulated with concentrations between 0 and 0.1 mol % oleic acid. Our major finding is that subdiffusive behavior over the 200 ns time scale is evident in systems at 340 K, with cholesterol diffusion being enhanced with increased oleic acid. Importantly, cholesterol and other species diffuse faster when radial densities indicate nearest neighbors include more cholesterol. We also find that, with the addition of oleic acid, the bilayer midplane and interfacial densities are reduced and there is a 3% decrease in total thickness occurring mostly near the hydrophilic interface at 300 K with reduced overall density at 340 K. Increased interdigitation occurs independent of oleic acid with a temperature increase. Slight ordering of the long non-hydroxy fatty acid of the ceramide occurs near the hydrophilic interface as a function of the oleic acid concentration, but no significant impact on hydrogen bonding is seen in the chosen oleic acid concentrations.

Lipid domain depletion at small localized bends imposed by a step geometry.

Natural processes in biological cells rely on molecules to be in the right place at the right time to maintain the dynamics of living processes. When lipids in bilayer membranes move and mix, they experience kinetic and thermodynamic barriers that affect the time scales of their locations and associations with each other. One of these barriers is that of the membrane shape. Using spin coating as a deposition technique, we formed multilamellar supported lipid bilayers on topologically patterned substrates with defined step rise heights of 13 and 27 nm measured by atomic force microscopy. Each step rise imposed two ridges on the lipid bilayers, and the ridge angles were measured by atomic force microscopy. The lipid composition of this system was 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and cholesterol (4:4:2), doped with a fluorescent lipid, which displays liquid-ordered-liquid-disordered (Lo-Ld) phase coexistence upon cooling to 25 °C. The DPPC-rich Lo domains in the upper bilayers were established to have boundaries and positions that responded to local forces. We found that these Lo domains were depleted at the location of each step rise. We employed an equation for local bending at a ridge and demonstrate that Lo domain densities at each rise correspond to these energies. Remarkably, an energy barrier greater than 1k(B)T is erected at a small deflection (1.3°) from planar geometry at the ridge, resulting in depletion of the majority of the optically visible Lo domains from the step rise. This work provides a means to design substrates that, in conjunction with supported lipid bilayers, provide defined localized topological energy barriers that can be used in biomembrane engineering. It also provides a method for easily analyzing the energetics of cusp-like shapes in cellular membrane structures.

Silica xerogel/aerogel-supported lipid bilayers: consequences of surface corrugation.

The objective of this paper was to review our recent investigations of silica xerogel and aerogel-supported lipid bilayers. These systems provide a format to observe relationships between substrate curvature and supported lipid bilayer formation, lipid dynamics, and lipid mixtures phase behavior and partitioning. Sensitive surface techniques such as quartz crystal microbalance and atomic force microscopy are readily applied to these systems. To inform current and future investigations, we review the experimental literature involving the impact of curvature on lipid dynamics, lipid and phase-separated lipid domain localization, and membrane-substrate conformations and we review our molecular dynamics simulations of supported lipid bilayers with the atomistic and molecular information they provide.

Coarse-grained modeling of lipids.

Molecular modeling of phospholipids on many scales has progressed significantly over the last years. Here we review several membrane models on intermediate to large length scales restricting ourselves to particle based coarse-grained models with implicit and explicit solvent. We explain similarities and differences as well as their connection to experiments and fine-grained models. We neglect any field descriptions on larger scales. We discuss then a few examples where we focus on studies of lipid phase behavior as well as supported lipid bilayers as these examples can only be meaningfully studied using large-scale models to date.

Coarse-grained modeling of interactions of lipid bilayers with supports.

We characterize the differences between supported and unsupported lipid bilayer membranes using a mesoscopic simulation model and a simple particle-based realization for a flat support on to which the lipids are adsorbed. We show that the nanometer roughness of the support affects membrane binding strength very little. We then compare the lipid distributions and pressure profiles of free and supported membranes. The surface localization of the proximal leaflet breaks the symmetry seen in a free bilayer, and we quantify the entropic penalty for binding and the increased lateral compression modulus.