DPPC Lipid Bilayer Research Articles

Low concentrated hydroxyectoine solutions in presence of DPPC lipid bilayers: A computer simulation study

The influence of hydroxyectoine on the properties of the aqueous solution in presence of DPPC lipid bilayers is studied via semi-isotropic constant pressure (NPT) Molecular Dynamics simulations. We investigate the solvent–co-solute behavior in terms of Kirkwood–Buff integrals as well as hydrogen bond life times for an increasing hydroxyectoine concentration up to 0.15mol/L. The observed preferential exclusion mechanism identifies hydroxyectoine as a kosmotropic osmolyte. Our findings with regard to the DPPC lipid bilayer indicate an increase of the surface pressure as well as the solvent accessible surface area in presence of higher hydroxyectoine concentrations. The results are in agreement to the outcome of recent experiments. With this study, we are able to validate the visibility of co-solute–solute–solvent effects for low and physiologically relevant osmolyte concentrations.

A Tale of Two Ions and their Membrane Interactions: Clearly the Same or Clearly Different?

A Tale of Two Ions and their Membrane Interactions: Clearly the Same or Clearly Different?

Simulations of the Phase Transition of DPPC Bilayer with and without DPH or TMA-DPH using CHARMM36

Early CHARMM all-atom force fields showed transition temperatures well above the experimental value of 315K. We simulated 100 ns for DPH and TMA-DPH dyes in DPPC lipid bilayers at atmospheric pressure and temperatures from 300-330K in 5K increments. Shifts were observed between 305K and 315K in area-per-headgroup, bilayer thickness, lipid-tail order parameters, and steady state dye fluorescence anisotropy. Dye effects on these membrane properties were negligible.

Ergosterol and Stigmasterol Interact with Phosphatidylcholine Lipid Bilayers Less Favorably than Cholesterol

Sterols are a class of membrane lipids that is important to maintain plasma membrane structure and functions in eukaryotic cells. The maximum solubility of sterol in a lipid bilayer is the highest mole fraction of sterol that can be incorporated into a lipid bilayer before sterol precipitates from the bilayer to form crystals. A higher maximum solubility indicates more favorable interactions between the sterol and lipid bilayer. In this study, the maximum solubilities of ergosterol and stigmasterol in DOPC and DSPC lipid bilayers were measured using light scattering and further confirmed using optical microscopy. We found that correlation function of scattering intensities from two independent detectors can be used to sensitively determine the solubility limits of sterols. The validity of our new technique was confirmed by measuring the solubility limit of cholesterol in DOPC and DPPC lipid bilayers. We found that the maximum solubilities of ergosterol and stigmasterol are higher in PC lipid bilayers with saturated chains (DSPC) than that in PC bilayers with unsaturated chains (DOPC). Compared with cholesterol, ergosterol and stigmasterol both have much lower solubility limits in PC lipid bilayers. Our results suggest that minor differences in sterol structure could result in large differences in sterol-PC interactions.

Identification of blocker binding site in mouse TRESK by molecular modeling and mutational studies

TWIK (tandem-pore domain weak inward rectifying K+)-related spinal cord K+ channel, TRESK, a member of the tandem-pore domain K+ channel family, is the most recently cloned K2P channel. TRESK is highly expressed in dorsal root ganglion neuron, a pain sensing neuron, which is a target for analgesics. In this study, a reliable 3D structure for transmembrane (TM) region of mouse TRESK (mTRESK) was constructed, and then the reasonable blocker binding mode of the protein was investigated. The 3D structure of the mTRESK built by homology modeling method was validated with recommend value of stereochemical quality. Based on the validated structure, K+ channel blocker-bound conformation was obtained by molecular docking and 5ns MD simulation with DPPC lipid bilayer. Our docking study provides the plausible binding mode of known blockers with key interacting residues, especially, F156 and F364. Finally, these modeling results were verified by experimental study with mutation from phenylalanine to alanine (F156A, F364A and F156A/F364A) at the TM2 and TM4. This is the first modeling study for TRESK that can provide structural information of the protein including ligand binding information. These results can be useful in structure based drug design for finding new blockers of the TRESK as potential therapeutic target of pain treatment.

Memprotmd: Adding the Grease to Membrane Protein Structures

Membrane protein structural biology is one of the key biochemical challenges. With continuous improvements to the methods used by structural biologists there is a predicted exponential growth in the number of membrane proteins structures. Nevertheless, these biological assemblies are usually resolved in the absence of the native lipid environment. Coarse-Grained molecular dynamics (CGMD) simulations provide a means for assessing the assembly and interactions of molecular complexes at a reduced level of representation. This method has been shown to accurately predict the position and orientation of proteins within a cell membrane. The results of these predictions are available in a database (http://sbcb.bioch.ox.ac.uk/cgdb). We are in the process of pipelining the procedure, so that new membrane protein structures are automatically inserted into a DPPC lipid bilayer on release from the Protein Data Bank (PDB). The CG simulations are then assessed for protein-lipid interactions, bilayer deformation, lipid diffusion and protein tilt. The resulting models are then refined to include more physiologically relevant lipid mixtures and subsequently converted to an atomistic resolution [1] to enable more detailed simulations of lipid protein interactions [2].[1] Stansfeld, JCTC, 7 (2011) 1157-1166.[2] Stansfeld, Biochemistry, 48 (2009) 10926-33.View Large Image | View Hi-Res Image | Download PowerPoint Slide

Concentration dependence of NaCl ion distributions around DPPC lipid bilayers

We study the coordination of excess NaCl to zwitterionic DPPC lipid bilayers using molecular dynamics simulations. We find that Na ions directly coordinate with the DPPC lipid carbonyl groups. As the number of excess ions increases, the number of coordinated ions increases, until it reaches a plateau at a ratio near 1 ion per every four lipids at 310 K, and 1 ion per every six lipids at 323 K. The area per lipid decreases as the number of excess ions is increased. For low number of ions per lipids (1:16 and 1:8), most Na ions are bound to the lipid carbonyls, while the Cl form an ionic cloud around the lipid choline groups. As a result of the Na binding, the lipid has an effective positive charge density. The residence time of Na ions bound to the lipid is longer than 40 ns, while Cl ions exchange faster than the nanoseconds timescale. We find that the bound Na ions replace ordered water around the carbonyls. The net linear charge density near the carbonyl groups stays positive, regardless of the presence of excess salt in the solution.

Structure and Phase Transformations of DPPC Lipid Bilayers in the Presence of Nanoparticles: Insights from Coarse-Grained Molecular Dynamics Simulations

In this article, we investigate fluid-gel transformations of a DPPC lipid bilayer in the presence of nanoparticles, using coarse-grained molecular dynamics. Two types of nanoparticles are considered, specifically a 3 nm hydrophobic nanoparticle located in the core of the bilayer and a 6 nm charged nanoparticle located at the interface between the bilayer and water phase. Both negatively and positively charged nanoparticles at the bilayer interface are investigated. We demonstrate that the presence of all types of nanoparticles induces disorder effects in the structure of the lipid bilayer. These effects are characterized using computer visualization of the gel phase in the presence of nanoparticles, radial distribution functions, and order parameters. The 3 nm hydrophobic nanoparticle immersed in the bilayer core and the positively charged nanoparticle at the bilayer surface have no effect on the temperature of the fluid-gel transformation, compared to the bulk case. Interestingly, a negatively charged hydrophobic nanoparticle located at the surface of the bilayer causes slight shift of the fluid-gel transformation to a lower temperature, compared to the bulk bilayer case.

Inhibition of Melittin Activity by Cholesterol, Unsaturated Lipid, and Negatively Charged Lipids Studied by Molecular Dynamics Simulation

Melittin is shown to cause membrane lyses. However, its lytic activity depends on the lipid composition of the membrane. Experiments have shown that the presence of some lipid components in the membrane can inhibit melittin's lytic power against the membrane. For the sake of atomistic details, molecular dynamics simulations was used to investigate the inhibition of melittin activity by cholesterol, unsaturated phospholipid (POPE), and negatively charged phospholipid (POPS). A pure DPPC lipid bilayer with melittin was simulated as a control, and significant disturbance of the bilayer by melittin was found. The order parameter of DPPC changed dramatically and a large curvature was observed in one of the membrane leaflets, probably leading to a future membrane rupture. The DPPC bilayer with cholesterol showed strong resistance to melittin: Melittin can hardly bind to the membrane surface. In the simulation with unsaturated lipid, melittin can only bind either its N or C terminal region to the bilayer, but the interaction between the body of melittin and the lipids is weak. Melittin binds strongly to negatively charged lipids; however, it cannot induce membrane curvature nor disruption. In above three simulations, C termini of melittin were observed to be able to bind to the membrane more easily than N termini. A deep and stable adsorption of melittin to the membrane requires the binding of both N and C-terminal regions to the membrabe. The tendency of melittin to aggregate was observed in all simulations, especially in the simulation containing cholesterol. This study provides insight into the possible mechanisms of the inhibition of melittin's lytic activity by different membrane components.

Properties and behaviour of tetracyclic allopsoralen derivatives inside a DPPC lipid bilayer model

Allopsoralens are angular psoralen derivatives presenting advantages over the parent compound because of monofunctional DNA-photobinding and consequent lower toxicity. Allopsoralen molecules with three different substituents and different protonation states were studied using the molecular dynamics technique. The location of these molecules when inside the lipid bilayer is of major importance because their photochemical properties can change with the environment. Also, the ability of psoralens to form photoadducts with unsaturated phospholipids depends on the preference of the molecules to locate themselves closer to the bilayer middle were the double bond functionality can be found. Herein we show that the allopsoralens tend to accumulate inside the lipid bilayer closer to the water interface when protonated or closer to the interface middle otherwise. Allopsoralens containing one amine terminated carbon chain tend to have different rotational and orientational behaviour and an orientation preference close to the ones shown by the lipids. The size and chemical nature of the substituent also affect the molecular mobility and capacity to interact with water molecules and the nitrogen or phosphorus atoms of the lipids.

A molecular dynamics study on heat conduction characteristics in DPPC lipid bilayer

In this paper, nonequilibrium molecular dynamics simulations were performed on a single component 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine lipid bilayer in order to investigate the thermal conductivity and its anisotropy. To evaluate the thermal conductivity, we applied a constant heat flux to the lipid bilayer along and across the membrane with ambient water. The contribution of molecular interaction to the heat conduction was also evaluated. Along the bilayer plane, there is little transfer of thermal energy by the interaction between lipid molecules as compared with the interaction between water molecules. Across the bilayer plane, the local thermal conductivity depends on the constituents (i.e., water, head group, and tail group of lipid molecule) that occupy the domain. Although the intramolecular transfer of thermal energy in the tail groups of lipid molecules works efficiently to promote high local thermal conductivity in this region, the highest thermal resistance appears at the center of lipid bilayer where acyl chains of lipid molecules face each other due to a loss of covalent-bond and low number density. The overall thermal conductivities of the lipid bilayer in the directions parallel and perpendicular to the lipid membrane have been compared, and it was found that the thermal conductivity normal to the membrane is higher than that along the membrane, but it is still smaller than that of bulk water.

Changes in transmembrane helix alignment by arginine residues revealed by solid-state NMR experiments and coarse-grained MD simulations.

Independent experimental and computational approaches show agreement concerning arginine/membrane interactions when a single arginine is introduced at selected positions within the membrane-spanning region of acetyl-GGALW(5)LALALAL(12)AL(14)ALALW(19)LAGA-ethanolamide, designated GWALP23. Peptide sequence isomers having Arg in position 12 or position 14 display markedly different behaviors, as deduced by both solid-state NMR experiments and coarse-grained molecular dynamics (CG-MD) simulations. With respect to the membrane normal of DOPC or DPPC lipid bilayer membranes, GWALP23-R14 shows one major state whose apparent average tilt is approximately 10 degrees greater than that of GWALP23. The presence of R14 furthermore induces bilayer thinning and peptide displacement to "lift" the charged guanidinium toward the bilayer surface. By contrast, GWALP23-R12 exhibits multiple states that are in slow exchange on the NMR time scale, with CG-MD simulations indicating two distinct positions with different screw rotation angles in the membrane, along with an increased tendency to exit the lipid bilayer.

A Modified Lipid Force Field for Charmm: Development and Application to Single-Celled Organism Membranes

Biological membranes form a barrier to protect the cell from its environment and selectively control the entrance/exit of small molecules. Molecular simulations of these biological membranes require an accurate lipid force field (a major component of the membrane). Previously, extensive ab initio quantum mechanical (QM) calculations have been used to improve the aliphatic portion of the CHARMM27 lipid force field. Although this was a significant improvement, the lipid head group required additional modifications to agree with experimental lipid bilayer deuterium order parameters (SCD) and solvation free energies. Therefore, we modified the atomic charges in the carbonyl-glycerol region and fit dihedral energy terms to high-level QM calculations and/or experiment. Molecular dynamics (MD) simulations with this new force field, referred to as CHARMM36 (C36), resulted in a significant improvement to the SCD's and water hydration for DPPC lipid bilayers. The calculated electrostatic profile and lipid bilayer surface tension decreased significantly. Consequently, the C36 force field resulted in excellent surface areas per lipid (and other properties) with NPT simulations, which is a significant improvement from the C27r force field that required constant area simulations (NPAT) to prevent some bilayers from laterally condensing. MD simulations of other pure lipid bilayers and monolayers also agreed favorably with experimental densities, monolayer surface tensions, and SCD's. The success of the C36 force field allowed for the study of complex lipid membranes in single-celled organisms. Model membranes were developed and simulated for yeast (six phospholipids, cholesterol, and 25-hydroxysterol) and Chlamydia (five unbranched lipids, a branced lipid, and cholesterol). These membranes are currently being used to study intracellular sterol transport and a porin protein that induces an immune response.

The Effects of High Voltages on the Morphology of a Dppc Lipid Bilayer

Biological membranes are often subject to large voltages compared to their small thickness, especially true in nerves where fluxes of ions and corresponding voltage changes are thought to be the main mechanism behind the nerve signal. Yet the effects that these voltages have on the phospholipids that makes up the membrane are largely unknown. Lipids of biological membranes are often charged or swittterionic, high electrical fields should be expected to have a large effect on their organization and thermodynamical properties. Fluorescence microscopy is utilized to image the effects of high voltage fields on the domain structure of a model system consisting of a Langmuir-Blodgett monolayer of phospholipids.

The Dynamic Stability of Cholesterol Clusters in DPPC Lipid Bilayers Studied by Molecular Dynamics Simulation

The dynamic stability of cholesterol clusters in DPPC lipid bilayers was investigated by MD simulation. Two parallel simulations were performed at 20 mole % of cholesterol: in one system, cholesterols were initially arranged as clusters, and in the other, cholesterols were randomly placed. Any two cholesterol molecules in the same monolayer are assigned to the same cluster if their lateral separation is less than a predetermined cutoff distance. The results show that cholesterol clusters in DPPC bilayers are unstable and are ready to disperse into individual cholesterol even at the early stage of the simulation. In the cluster system, the average size of cholesterol cluster decreases monotonously and the total number of clusters increases with time, approaching the corresponding values of the random system. In addition, cholesterols in cluster experience more water exposure, and this unfavorable exposure is reduced when individual cholesterols are surrounded by DPPC molecules. The result is consistent with the Umbrella Model, which suggests that, driven by hydrophobic interactions, cholesterols have a strong tendency to avoid forming cluster in a lipid bilayer.

Spontaneous Formation of a Barrel-Stave Pore in a Coarse-Grained Model of the Synthetic LS3 Peptide and a DPPC Lipid Bilayer

We perform long-time-scale coarse-grained molecular dynamics simulations of the synthetic amphiphilic LS3 peptide interacting with a DPPC lipid bilayer. Our studies show that within several microseconds, the peptide assembles in a trans-membrane barrel-stave pore. The pore consists of six peptides and has an inner diameter of about 5.2 A, which is comparable to earlier experimental and more detailed atomistic studies. Other structures such as three-, four-, and five-member bundles are also observed.

Coarse-Grained Molecular Dynamics Study of Cyclic Peptide Nanotube Insertion into a Lipid Bilayer

Coarse-grained (CG) molecular dynamics (MD) simulations are performed to study the insertion of cyclic peptide nanotubes into cell membranes and to examine whether cyclic peptide nanotubes can function as an ion channel and thereby as an antibacterial agent. To do so, the two coarse-grained (CG) models for lipid molecules and for proteins developed by Marrink et al. (J. Phys. Chem. B 2004, 108, 750) and by Shih et al. (J. Phys. Chem. B 2006, 110, 3674), respectively, were extended and modified. These CG models were verified by performing CG MD and all-atom (AA) MD simulations for a cyclic peptide nanotube, 8 x cyclo[(-d-Ala-l-Glu-d-Ala-l-Gln-)2], in water and by comparing the results from the two simulations. Comparison between static and dynamic (water transport) properties obtained from both simulations shows good agreement. To study nanotube insertion, a CG cyclic peptide nanotube, 8 x cyclo[(-Trp-d-Leu-)4], was prepared above the surface of a CG DPPC lipid bilayer, restrained with constraints, and equilibrated, and then a series of CG MD simulations were carried out by lifting the constraints imposed on the nanotube. The CG MD simulations show that the cyclic peptide nanotube spontaneously inserts into and reorients inside the lipid bilayer. After insertion, the long axis of the cyclic peptide nanotube is aligned approximately perpendicular to the bilayer plane indicating that the nanotube can function as an ion channel and as an antibacterial agent. Tilt structures of the cyclic peptide nanotubes inside the lipid bilayer are found to be in agreement with experiment and earlier AA simulations. Lipid flip-flop, a migration of lipid molecules from one leaflet to the other leaflet of the lipid bilayer, is also observed from the CG MD simulations. Finally, the CG MD simulations reveal that a lipid headgroup can be inserted into the cyclic peptide nanotube. This process is confirmed by an AA MD simulation.

Modelling the behavior of 5-aminolevulinic acid and its alkyl esters in a lipid bilayer

5-Aminolevulinic acid (5ALA) and ester derivates thereof are used as prodrugs in photodynamic therapy (PDT). The behavior of 5ALA and three esters of 5ALA in a DPPC lipid bilayer is investigated. In particular, the methyl ester displays a very different free energy profile, where the highest barrier is located in the region with highest lipid density, while the others have their peak in the middle of the membrane, and also displays a considerably lower permeability coefficient than neutral 5ALA and the ethyl ester. The zwitterion of 5ALA has the highest permeability constant, but a significant free energy minimum in the polar head-group region renders an accumulation in this region.

Role of Nanomechanical Properties in the Tribological Performance of Phospholipid Biomimetic Surfaces

The role of phospholipid bilayers in controlling and reducing frictional forces between biological surfaces is investigated by three complementary experiments: friction forces are measured using a homemade tribometer, mechanical resistance to indentation is measured by AFM, and lipid bilayer degradation is controlled in situ during friction testing using fluorescence microscopy. DPPC lipid bilayers in the solid phase generate friction coefficients as low as 0.002 (comparable to that found for cartilage) that are stable through time. DOPC bilayers formed by the vesicle fusion method or the adsorption of mixed micelles generate higher friction coefficients. These coefficients increased through time, during which the bilayers degraded. The friction coefficient is correlated with the force needed to penetrate the bilayer with the AFM tip. With only one bilayer in the contact region, the friction increased to a similar value of about 0.08 for the DPPC and DOPC. Our study therefore shows that good mechanical stability of the bilayers is essential and suggests that the low friction coefficient is ensured by the hydration layers between adjacent lipid bilayers.

Molecular dynamics simulations of DiI-C18(3) in a DPPC lipid bilayer

We performed a 40 ns simulation of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI-C18(3)) in a 1,2-dipalmitoyl-sn-glycero-3-phosphatidyl choline (DPPC) bilayer in order to facilitate interpretation of lipid dynamics and membrane structure from fluorescence lifetime, anisotropy, and fluorescence correlations spectroscopy (FCS). Incorporation of DiI of 1.6 to 3.2 mol% induced negligible changes in area per lipid but detectable increases in bilayer thickness, each of which are indicators of membrane structural perturbation. The DiI chromophore angle was 77 +/- 17 degrees with respect to the bilayer normal, consistent with rotational diffusion inferred from polarization studies. The DiI headgroup was located 0.63 nm below the lipid head group-water interface, a novel result in contrast to some popular cartoon representations of DiI but consistent with DiI's increase in quantum yield when incorporated into lipid bilayers. Importantly, the fast component of rotational anisotropy matched published experimental results demonstrating that sufficient free volume exists at the sub-interfacial region to support fast rotations. Simulations with non-charged DiI head groups exhibited DiI flip-flop, demonstrating that the positively-charged chromophore stabilizes the orientation and location of DiI in a single monolayer. DiI induced detectable changes in interfacial properties of water ordering, electrostatic potential, and changes in P-N vector orientation of DPPC lipids. The diffusion coefficient of DiI (9.7 +/- 0.02 x 10(-8) cm2 s(-1)) was similar to the diffusion of DPPC molecules (10.7 +/- 0.04 x 10(-8) cm2 s(-1)), supporting the conclusion that DiI dynamics reflect lipid dynamics. These results provide the first atomistic level insight into DiI dynamics, results essential in elucidating lipid dynamics through single molecule fluorescence studies.