Understanding the solvent polarity effects on surfactant-capped nanoparticles.

Understanding the molecular interactions between suspended nanoparticles (NPs) and the suspending solvent fluid may provide a useful avenue to create and to study exotic NP ensembles. This study focused on using a coarse-grained computational model to investigate the molecular interactions between oleate-capped NPs in various solvents, and to relate the results to experimental features of solvent-suspended, oleate-capped CdSe quantum dots (QDs). The QDs were modeled as a closed-shell fullerene molecule with an oleate-like ligand attached to each vertex. Solvent polarity was found to correlate to the simulation and experimental results more strongly than either dielectric constant or dipole moment. Computational results showed that the nonpolar solvents of hexane, toluene, and benzene (polarity index E(T)(N) < 0.120) kept NPs in suspension and solvated the oleate chains such that the oleate layer swelled to full extension. In contrast, as the most polar solvent tested (E(T)(N) = 1.000), water caused NPs to aggregate and precipitate. It partially solvated the oleate chains and compressed the layer to 86% of full extension. For solvents of intermediate polarity like ethanol, acetone, and chloroform, the oleate layer swelled with decreasing polarity index values, with rapid swelling occurring close to E(T)(N) = 0.307 (~50:50 vol % chloroform/acetone) below which QDs were colloidally stable. This study represents the first attempt to delineate the solvent effect on surfactant-coated NP hydrodynamic size, colloidal stability, and aggregation behavior.

The role of fatty acid unsaturation in minimizing biophysical changes on the structure and local effects of bilayer membranes.

Studying the effects of saturated and unsaturated fatty acids on biological and model (liposomes) membranes could provide insight into the contribution of biophysical effects on the cytotoxicity observed with saturated fatty acids. In vitro experiments suggest that unsaturated fatty acids, such as oleate and linoleate, are less toxic, and have less impact on the membrane fluidity. To understand and assess the biophysical changes in the presence of the different fatty acids, we performed computational analyses of model liposomes with palmitate, oleate, and linoleate. The computational results indicate that the unsaturated fatty acid chain serves as a membrane stabilizer by preventing changes to the membrane fluidity. Based on a Voronoi tessellation analysis, unsaturated fatty acids have structural properties that can reduce the lipid ordering within the model membranes. In addition, hydrogen bond analysis indicates a more uniform level of membrane hydration in the presence of oleate and linoleate as compared to palmitate. Altogether, these observations from the computational studies provide a possible mechanism by which unsaturated fatty acids minimize biophysical changes and protect the cellular membrane and structure. To corroborate our findings, we also performed a liposomal leakage study to assess how the different fatty acids alter the membrane integrity of liposomes. This showed that palmitate, a saturated fatty acid, caused greater destabilization of liposomes (more "leaky") than oleate, an unsaturated fatty acid.

Molecular dynamics study on the stabilization of dehydrated lipid bilayers with glucose and trehalose.

In this study, we use molecular dynamics simulations to investigate and compare the interactions of DPPC bilayers with and without saccharides (glucose or trehalose) under dehydrated conditions. Results from the simulations indicate that unilamellar bilayers lose their structural integrity under dehydrated conditions in the absence of saccharides; however, in the presence of either glucose or trehalose, the bilayers maintain their stability. Hydrogen bond analysis shows that the saccharide molecules displace a significant amount of water surrounding the lipid headgroups. At the same time, the additional hydrogen bonds formed between water and saccharide molecules help to maintain a hydration layer on the lipid bilayer interface. On the basis of the hydrogen bond distributions, trehalose forms more hydrogen bonds with the lipids than glucose, and it is less likely to interact with neighboring saccharide molecules. These results suggest that the interaction between the saccharide and lipid molecules through hydrogen bonds is an essential component of the mechanism for the stabilization of lipid bilayers.

Experimental and computational studies investigating trehalose protection of HepG2 cells from palmitate-induced toxicity.

Understanding the mechanism of saturated fatty acid-induced hepatocyte toxicity may provide insight into cures for diseases such as obesity-associated cirrhosis. Trehalose, a nonreducing disaccharide shown to protect proteins and cellular membranes from inactivation or denaturation caused by different stress conditions, also protects hepatocytes from palmitate-induced toxicity. Our results suggest that trehalose serves as a free radical scavenger and alleviates damage from hydrogen peroxide secreted by the compromised cells. We also observe that trehalose protects HepG2 cells by interacting with the plasma membrane to counteract the changes in membrane fluidity induced by palmitate. The experimental results are supported by molecular dynamics simulations of model cell membranes that closely reflect the experimental conditions. Simulations were performed to understand the specific interactions between lipid bilayers, palmitate, and trehalose. The simulations results reveal the early stages of how palmitate induces biophysical changes to the cellular membrane and the role of trehalose in protecting the membrane structure.

Molecular characterization of gel and liquid-crystalline structures of fully hydrated POPC and POPE bilayers.

Molecular dynamics simulations were used for a comprehensive study of the structural properties of monounsaturated POPC and POPE bilayers in the gel and liquid-crystalline state at a number of temperatures, ranging from 250 to 330 K. Though the chemical structures of POPC and POPE are largely similar (choline versus ethanolamine headgroup), their transformation processes from a gel to a liquid-crystalline state are contrasting. In the similarities, the lipid tails for both systems are tilted below the phase transition and become more random above the phase transition temperature. The average area per lipid and bilayer thickness were found less sensitive to phase transition changes as the unsaturated tails are able to buffer reordering of the bilayer structure, as observed from hysteresis loops in annealing simulations. For POPC, changes in the structural properties such as the lipid tail order parameter, hydrocarbon trans-gauche isomerization, lipid tail tilt-angle, and level of interdigitation identified a phase transition at about 270 K. For POPE, three temperature ranges were identified, in which the lower one (270-280 K) was associated with a pre-transition state and the higher (290-300 K) with the post-transition state. In the pre-transition state, there was a significant increase in the number of gauche arrangements formed along the lipid tails. Near the main transition (280-290 K), there was a lowering of the lipid order parameters and a disappearance of the tilted lipid arrangement. In the post-transition state, the carbon atoms along the lipid tails became less hindered as their density profiles showed uniform distributions. This study also demonstrates that atomistic simulations of current lipid force fields are capable of capturing the phase transition behavior of lipid bilayers, providing a rich set of molecular and structural information at and near the main transition state.

Molecular studies of the gel to liquid-crystalline phase transition for fully hydrated DPPC and DPPE bilayers.

Molecular dynamics simulations were used for a comprehensive study of the structural properties of saturated lipid bilayers, DPPC and DPPE, near the main phase transition. Though the chemical structure of DPPC and DPPE are largely similar (they only differ in the choline and ethanolamine groups), their transformation process from a gel to a liquid-crystalline state is contrasting. For DPPC, three distinct structures can be identified relative to the melting temperature (Tm): below Tm with "mixed" domains consisting of lipids that are tilted with partial overlap of the lipid tails between leaflet; near Tm with a slight increase in the average area per lipid, resulting in a rearrangement of the lipid tails and an increase in the bilayer thickness; and above Tm with unhindered lipid tails in random motion resulting in an increase in %gauche formed and increase in the level of interdigitation between lipid leaflets. For DPPE, the structures identified were below Tm with "ordered" domains consisting of slightly tilted lipid tails and non-overlapping lipid tails between leaflets, near Tm with minimal rearrangement of the lipids as the bilayer thickness reduces slightly with increasing temperature, and above Tm with unhindered lipid tails as that for DPPC. For DPPE, most of the lipid tails do not overlap as observed to DPPC, which is due to the tight packing of the DPPE molecules. The non-overlapping behavior of DPPE above Tm is confirmed from the density profile of the terminal carbon atoms in each leaflet, which shows a narrow distribution near the center of the bilayer core. This study also demonstrates that atomistic simulations are capable of capturing the phase transition behavior of lipid bilayers, providing a rich set of molecular and structural information at and near the transition state.

Molecular study of the diffusional process of DMSO in double lipid bilayers.

As a way to quantify the diffusion process of molecular compounds through biological membranes, we investigated in this study the dynamics of DMSO through an 1,2-Dipalmitoyl-sn-Glycero-3-Phosphocholine (DPPC) bilayer system. To properly account for the diffusion of DMSO due to a concentration gradient, a double DPPC bilayer was setup for our simulations. In such configuration, the aqueous phases can be explicitly associated with the extra and intracellular domains of the membrane, which is seldom the case in studies of single lipid bilayer due to the periodicity imposed by the simulations. DMSO molecules were initially contained in one of the aqueous phases (extracellular region) at a concentration of 5 wt.%. Molecular dynamics simulation was performed in this system for 95 ns at 350 K and 1 bar. The simulations showed that although many DMSO molecules penetrated the lipid bilayer, only about 10% of them crossed the bilayer to reach the other aqueous phase corresponding to the intracellular region of the membrane. The simulation time considered was insufficient to reach equilibrium of the DMSO concentration between the aqueous phases. However, the simulations provided sufficient information to estimate parameters to apply Fick's Law to model the diffusion process of the system. Using this model, we predicted that for the time considered in our simulation, the concentration of DMSO in the intracellular domain should have been about half of the actual value obtained. The model also predicted that equilibrium of the DMSO concentration in the system would be reached after about 2000 ns, approximately 20 times longer than the performed simulation.

Molecular simulation study of structural and dynamic properties of mixed DPPC/DPPE bilayers.

Molecular dynamics simulations have been used to study structural and dynamic properties of fully hydrated mixed 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) bilayers at 0, 25, 50, 75, and 100 mol % DPPE. Simulations were performed for 50 ns at 350 K and 1 bar for the liquid-crystalline state of the mixtures. Results show that the average area per headgroup reduces from 0.65 +/- 0.01 nm(2) in pure DPPC to 0.52 +/- 0.01 nm(2) in pure DPPE systems. The lipid tails become more ordered with increasing DPPE concentration, resulting in a slight increase in membrane thickness (3.43 +/- 0.01 nm in pure DPPC to 4.00 +/- 0.01 nm in pure DPPE). The calculated area per headgroup and order parameter for pure DPPE deviates significantly from available experimental measurements, suggesting that the force field employed requires further refinement. In-depth analysis of the hydrogen-bond distribution in DPPE molecules shows that the amine groups strongly interact with the phosphate and carbonyl groups through inter/intramolecular hydrogen bonds. This yields a bilayer structure with DPPE headgroups preferentially located near the lipid phosphate and ester oxygens. It is observed that increasing DPPE concentrations causes competitive hydrogen bonding between the amine groups (hydrogen-donor) and the phosphate/carbonyl groups or water (hydrogen-acceptor). Due to the increasing number of hydrogen-donors from DPPE molecules with increasing concentration, DPPE becomes more hydrated. Trajectory analysis shows that DPPE molecules in the lipid mixtures move laterally and randomly around the membrane surface and the movement becomes more localized with increasing DPPE concentrations. For the conditions and simulation time considered, no aggregation or phase separation was observed between DPPC and DPPE.