Simulations Of Lipid Bilayers Research Articles

Characterization of Electron Density Profiles and Area Per Lipid from MD Simulation of Large Undulating Bilayers

Determination of the electron density profile (EDP) and area per lipid (AL) from MD simulations of large lipid bilayers requires the characterization and isolation of the mesoscopic undulation dynamics. Typically, for small, flat bilayer patches, EDPs are calculated assuming a uniform bilayer normal across the trajectory. When common EDP algorithms are applied to larger systems, the undulations convolve an averaging function with the underlying

Oxidative Damage in Lipid Bilayers: A Reactive Molecular Dynamics Study

Current simulations of lipid bilayers focus on their structural and compositional properties. Chemical reactivity between cell membranes and extra cellular species is an unexplored field for molecular dynamics. To explore this new area of research, we have simulated a lipid bilayer composed of 200 POPC lipids (along with 50 waters per lipid) and its reaction with a simple peroxide for 8 ns using Reactive Molecular Dynamics (Purdue Reax). The specific chemical pathways of oxidative damage can be determined from these simulations and a greater insight into the process can be achieved.

Development and Application of Non-Additive Force Fields for Molecular Simulations of Lipid Bilayers and Integral Membrane Proteins

Molecular simulations today are applied across many scientific disciplines. Complementing experiment, these tools afford a molecular-level understanding and interpretation of physico-chemical processes at resolutions and timescales difficult or practically inaccessible to experiment. At the heart of such methods is the description of interactions between atoms and molecules, the force field. Traditionally, non-reactive force fields have treated electrostatic interactions using an additive, Coulomb model between fixed partial charges on atomic sites. Though quite successful, there has been conjecture as to the effects of incorporating non-additivity in classical force fields, particularly in biological systems. Over the last several decades, attempts to incorporate electrostatic non-additivity in the form of inducible dipole interactions or dynamically varying partial charges have provided a vast body of knowledge that has aided in the development of a new class of force fields attempting to explicitly account for non-additive effects. We will present our recent work in developing one such class of models, charge equilibration force fields, and applications of such models to aqueous solution interfaces, membrane bilayers and simple integral membrane peptides such as the gramicidin A bacterial channel, and recent work on modeling of protein-ligand interaction free energetics.

Liquid-Ordered Phase Formation in Cholesterol/Sphingomyelin Bilayers: All-Atom Molecular Dynamics Simulations

This paper reports an all-atom molecular dynamics simulation of lipid bilayers with different cholesterol/sphingomyelin molar ratios. Our results reveal structural and dynamic changes suggesting the random distribution of lipids along the bilayer planes is supplanted at cholesterol concentrations above 30 mol % by the formation of a liquid-ordered phase, which is thought to be the precursor to lipid raft formation. The packing of molecules in the bilayer is shown to be associated with the hydrogen bonding between cholesterol and sphingomyelin. The molecules tend to migrate toward distributions in which the sphingomyelin molecule forms on average one hydrogen bond with a cholesterol molecule. The threshold for activation of this packing trend coincides with the experimentally determined threshold membrane activity of a cytolytic protein ostreolysin, which binds to and permeabilizes cholesterol-sphingomyelin bilayers containing more than 30 mol % cholesterol.

Undulation Contributions to the Area Compressibility in Lipid Bilayer Simulations

It is here shown that there is a considerable system size-dependence in the area compressibility calculated from area fluctuations in lipid bilayers. This is caused by the contributions to the area fluctuations from undulations. This is also the case in experiments. At present, such a contribution, in most cases, is subtracted from the experimental values to obtain a true area compressibility. This should also be done with the simulation values. Here, this is done by extrapolating area compressibility versus system size, down to very small (zero) system size, where undulations no longer exist. The area compressibility moduli obtained from such simulations do not agree with experimental true area compressibility moduli as well as the uncorrected ones from contemporary or earlier simulations, but tend, instead, to be ∼50% too large. As a byproduct, the bending modulus can be calculated from the slope of the compressibility modulus versus system-size. The values obtained in this way for the bending modulus are then in good agreement with experiment.

Experimental verification of lipid bilayer structure through multi-scale modeling

Great progress has been made in applying coarse-grain molecular dynamics (CGMD) simulations to the investigation of membrane biophysics. In order to validate the accuracy of CGMD simulations of membranes, atomistic scale detail is necessary for direct comparison to structural experiments. Here, we present our strategy for verifying CGMD lipid bilayer simulations. Through reverse coarse graining and subsequent calculation of the bilayer electron density profile, we are able to compare the simulations to our experimental low angle X-ray scattering (LAXS) data. In order to determine the best match to the experimental data, atomistic simulations are run at a range of areas (in the NP NAT ensemble), starting from distinct configurations extracted from the CGMD simulation (run in the NPT ensemble). We demonstrate the effectiveness of this procedure with two small, single-component bilayers, and suggest that the greater utility of our algorithm will be for CGMD simulations of more complex structures.

Calculation of the electrostatic potential of lipid bilayers from molecular dynamics simulations: Methodological issues

The electrostatic properties of lipid membranes are of profound importance as they are directly associated with membrane potential and, consequently, with numerous membrane-mediated biological phenomena. Here we address a number of methodological issues related to the computation of the electrostatic potential from atomic-scale molecular dynamics simulations of lipid bilayers. We discuss two slightly different forms of Poisson equation that are normally used to calculate the membrane potential: (i) a classical form when the potential and the electric field are chosen to be zero on one of the sides of a simulation box and (ii) an alternative form, when the potential is set to be the same on the opposite sides of a simulation box. Both forms differ by a position-dependent correction term, which has been shown to be proportional to the overall dipole moment of a bilayer system (for neutral systems). For symmetric bilayers we demonstrate that both approaches give essentially the same potential profiles, provided that simulations are long enough (a production run of at least 100 ns is required) and that fluctuations of the center of mass of a bilayer are properly accounted for. In contrast, for asymmetric lipid bilayers, the second approach is no longer appropriate due to a nonzero net dipole moment across a simulation box with a single asymmetric bilayer. We demonstrate that in this case the electrostatic potential can adequately be described by the classical form of Poisson equation, provided that it is employed in conjunction with tin-foil boundary conditions, which exactly balance a nonzero surface charge of a periodically replicated multibilayer system. Furthermore, we show that vacuum boundary conditions give qualitatively similar potential profiles for asymmetric lipid bilayers as compared to the conventional periodic boundaries, but accurate determination of the transmembrane potential difference is then hindered due to detachment of some water dipoles from bulk aqueous solution to vacuum.

Comparison of the Extended Isotropic Periodic Sum and Particle Mesh Ewald Methods for Simulations of Lipid Bilayers and Monolayers

3D-IPS/DFFT is an extension of the three-dimensional isotropic periodic sum (3D-IPS) for evaluation of electrostatic and Lennard-Jones interactions in heterogeneous systems; it utilizes a discrete fast Fourier transform (DFFT) for efficient calculation of the IPS potential with a large local region radius. The method is demonstrated to be highly accurate for simple bulk fluids, liquid/liquid and liquid/vapor interfaces, and lipid bilayers and monolayers. Values for r(C) (the cutoff distance for direct evaluation of pairs) and R(C) (the local region radius) equal to 10 A and twice the longest edge of the periodic cell, respectively, provide excellent efficiency and accuracy. Dimyristoylphosphatidylcholine (DMPC) monolayers simulated with the CHARMM (Chemistry at HARvard Molecular Mechanics) C27r lipid parameter set and 3D-IPS/DFFT yield surface tensions approximately 8 dyn/cm higher than those simulated using particle mesh Ewald (PME), and with experiment. In contrast, surface tensions for DMPC bilayers are 16 dyn/cm/leaflet with both 3D-IPS/DFFT (r(C) = 10 and 12 A) and PME (r(C) = 12 A). This indicates that PME (r(C) = 12 A) may be used for simulations of bilayers, but not monolayers, and that the large bilayer surface tension arising from C27r is incorrect.

A Novel Analysis Technique For Determining Area Per Lipid And Electron Density Profiles From Large Lipid Bilayer Molecular Dynamics Simulations

Determination of the area per lipid (AL) and electron density profiles (EDP) from molecular dynamics simulations of lipid bilayers is complicated in large systems where mesoscopic undulations develop. Typically, AL is determined by a projection onto the xy-plane (often using the periodic box dimensions or Voronoi tessellation). However, this approach underestimates AL by not accounting for the out-of-plane undulations. As an alternative, we have used interpolated surfaces to more accurately characterize the simulated AL. We apply a 2-dimensional spatial filter with a frequency response optimized to a characteristic wave-number, q0, as determined by Lindahl and Edholm. In so doing, the interpolated bilayer surface captures the desired low-q modes of undulation while damping the undesirable high-q protrusions. AL values from our filtered trajectories yield an increase of 1-3 A2 over that of the traditional calculations. Regarding EDPs, current algorithms parse the atoms into bins orthogonal to the normal of the bilayer. In large bilayer simulations, undulations introduce heterogeneous sampling in the z-slices. This heterogeneity convolves an averaging function with the electron density, resulting in a smoothed profile, an artifact of the calculation. Subsets of the simulated bilayer, however, with lengths that are less than the characteristic wavelength corresponding to q0, are locally flat. By transforming each local patch to a coordinate frame whose z-axis is parallel to the normal of the plane of that patch, we can implement homogeneous z-slicing to accurately determine the EDP.

CHARMM-GUI Membrane Builder for Mixed Bilayers and Its Application to Yeast Membranes

Most biological membranes are composed of many different kinds of lipid, and can be characterized by the composition of the lipids. Although more and more researchers have shown their interests in molecular dynamics simulation of lipid bilayer or protein-membrane complex system, the setup of such system remains quite challenging for even relatively experienced researchers. In the previous work [1], we have shown that the setup of molecular dynamics simulation for protein-membrane complex can be dramatically simplified by automating the process and providing intuitive and straightforward user interface. In this work, we have further elaborated the process to include 25 different kinds of lipid, which makes it possible to build more biologically relevant lipid bilayers, and we also added the facility to make a lipid bilayer system alone. The efficacy of the web interface at the CHARMM-GUI website [2] has been tested by building and simulating lipid bilayer systems that resemble yeast membrane, which is composed of cholesterol, DPPC, DOPC, POPE, POPA, and POPS. In this work, we will present the usages of the mixed bilayer generation in Membrane Builder and the simulation results of the yeast membrane systems.

Characterization of the outer membrane protein OprF of Pseudomonas aeruginosa in a lipopolysaccharide membrane by computer simulation

The N-terminal domain of outer membrane protein OprF of Pseudomonas aeruginosa forms a membrane spanning eight-stranded antiparallel beta-barrel domain that folds into a membrane channel with low conductance. The structure of this protein has been modeled after the crystal structure of the homologous protein OmpA of Escherichia coli. A number of molecular dynamics simulations have been carried out for the homology modeled structure of OprF in an explicit molecular model for the rough lipopolysaccharide (LPS) outer membrane of P. aeruginosa. The structural stability of the outer membrane model as a result of the strong electrostatic interactions compared with simple lipid bilayers is restricting both the conformational flexibility and the lateral diffusion of the porin in the membrane. Constricting side-chain interactions within the pore are similar to those found in reported simulations of the protein in a solvated lipid bilayer membrane. Because of the strong interactions between the loop regions of OprF and functional groups in the saccharide core of the LPS, the entrance to the channel from the extracellular space is widened compared with the lipid bilayer simulations in which the loops are extruding in the solvent. The specific electrostatic signature of the LPS membrane, which results in a net intrinsic dipole across the membrane, is found to be altered by the presence of OprF, resulting in a small electrically positive patch at the position of the channel.

Role of phosphatidylglycerols in the stability of bacterial membranes

An extensive 100-ns molecular dynamics simulation of lipid bilayer composed of mixture of phosphatidylethanolamine (PE) and phosphatidylglycerol (PG) was performed to elucidate the role of PGs to the stability of bacterial membranes. In addition, a control simulation of pure PE over 150 ns was performed. We observed that PGs decrease both the PE headgroup protrusions into the water phase, and the PE headgroup motion along bilayer normal. The above effects are caused by stronger inter-lipid interactions in the mixed bilayer: the number of hydrogen bonds created by PEs is 34% higher in the mixed than in the pure bilayer. Another contribution is due to the numerous ion-mediated inter-lipid links, which strongly enhance interface stability. That provides a plausible mechanism for preventing lipid desorption from the membrane, for example, under the influence of an organic solvent. A more compact and less dynamic interface structure also decreases membrane permeability. That provides a possible mechanism for stabilizing, e.g., bacterial membranes.

Replacing the Cholesterol Hydroxyl Group with the Ketone Group Facilitates Sterol Flip-Flop and Promotes Membrane Fluidity

The 3alpha-hydroxyl group is a characteristic structural element of all membrane sterol molecules, while the 3-ketone group is more typically found in steroid hormones. In this work, we investigate the effect of substituting the hydroxyl group in cholesterol with the ketone group to produce ketosterone. Extensive atomistic molecular dynamics simulations of saturated lipid membranes with either cholesterol or ketosterone show that, like cholesterol, ketosterone increases membrane order and induces condensation. However, the effect of ketosterone on membrane properties is considerably weaker than that of cholesterol. This is largely due to the unstable positioning of ketosterone at the membrane-water interface, which gives rise to a small but significant number of flip-flop transitions, where ketosterone is exchanged between membrane leaflets. This is remarkable, as flip-flop motions of sterol molecules have not been previously reported in analogous lipid bilayer simulations. In the same context, ketosterone is found to be more tilted with respect to the membrane normal than cholesterol. The atomic level mechanism responsible for the increase of the steroid tilt and the promotion of flip-flops is the decrease in polar interactions at the membrane-water interface. Interactions between lipids or water and the ketone group are found to be weaker than in the case of the hydroxyl group, which allows ketosterone to penetrate through the hydrocarbon region of a membrane.

A meso‐scale analysis of lipid bilayers with the dissipative particle dynamics method: Thermally fluctuating interfaces

AbstractWe present a meso‐scale simulation of lipid bilayers with the dissipative particle dynamics (DPD) method. The spectrums of the thermal undulation are analysed and the bending rigidity of the lipid bilayers is calculated. In order to define the position of the membrane, we apply a definition of the interface which has been newly proposed by Kikugawa et al. (Comput. Fluids 2007; 36:69–76). We show the applicability of this method to the lipid bilayer system. By means of this definition, the roughness of the extracted interface can be varied and this effect is investigated. The spectral intensity is shown as a function of the undulatory wavenumber q. The spectral intensity in large‐q regions is affected by the roughness of the interface. However, we find that the spectral intensity in small‐q regions, where the bending rigidity can be calculated, is hardly affected. Moreover, the undulation spectrums show q−4 behaviour in small‐q regions, which agrees with the theoretical prediction. The effects of the size of the computational cell are also investigated. All spectrums obtained in the differently sized cells agree well, although the observable range of the wavenumber depends on the cell size. The bending rigidity calculated by spectral intensity from the largest cell is in good agreement with experiments and molecular dynamics simulations in the literature. Copyright © 2007 John Wiley & Sons, Ltd.

Improved dissipative particle dynamics simulations of lipid bilayers

The authors introduce a new parameterization for the dissipative particle dynamics simulations of lipid bilayers. In this parameterization, the conservative pairwise forces between beads of the same type in two different hydrophobic chains are chosen to be less repulsive than the water-water interaction, but the intrachain bead interactions are the same as the water-water interaction. For a certain range of parameters, the new bilayer can only be stretched up to 30% before it ruptures. Membrane tension, density profiles, and the in-plane lipid diffusion coefficient of the new bilayer are discussed in detail. They find two kinds of finite size effects that influence the membrane tension: lateral finite size effects, for which larger membranes rupture at a smaller stretch, and transverse finite size effects, for which tensionless bilayers are more compact in larger systems. These finite size effects become rather small when the simulation box is sufficiently large.

1530 超音波による分子の細胞膜通過機構 : 分子動力学シミュレーション(S32 DDSをめざした音響波や渦の応用,S32 DDSをめざした音響波や渦の応用)

Cell membrane permeabilization technique utilizing ultrasound and micro- nano- bubbles (i.e. sonoporation) is a promising way of drug and gene delivery. The mechanisms of the permeabilization and subsequent molecular transport across the membrane are underlying the development of the technique for clinical applications. We thereby have studied the mechanisms in the molecular level by molecular dynamics (MD) simulations of lipid bilayers, which are fundamental of all biological cell membranes. Firstly, we performed MD simulations of structural changes of the bilayer induced by shock wave and revealed the resulting collapse and rebound of the bilayer followed by water penetration into the hydrophobic region of the bilayer. Next, we studied the water pore formation resulted from the water penetration into the hydrophobic region. It was found that the water pore is formed within several nanoseconds when large amount of water molecules are existed in the hydrophobic region. Finally, we analyzed the diffusion of anti-cancer drug in the water pore and deduced that the water pore induced by the action of shock wave may be one of the processes of drug delivery in the presence of shock waves.

Investigation of Finite System-Size Effects in Molecular Dynamics Simulations of Lipid Bilayers

In the absence of external stress, the surface tension of a lipid membrane vanishes at equilibrium, and the membrane exhibits long wavelength undulations that can be described as elastic (as opposed to tension-dominated) deformations. These long wavelength fluctuations are generally suppressed in molecular dynamics simulations of membranes, which have typically been carried out on membrane patches with areas <100 nm2 that are replicated by periodic boundary conditions. As a result, finite system-size effects in molecular dynamics simulations of lipid bilayers have been subject to much discussion in the membrane simulation community for several years, and it has been argued that it is necessary to simulate small membrane patches under tension to properly model the tension-free state of macroscopic membranes. Recent hardware and software advances have made it possible to simulate larger, all-atom systems allowing us to directly address the question of whether the relatively small size of current membrane simulations affects their physical characteristics compared to real macroscopic bilayer systems. In this work, system-size effects on the structure of a DOPC bilayer at 5.4 H2O/lipid are investigated by performing molecular dynamics simulations at constant temperature and isotropic pressure (i.e., vanishing surface tension) of small and large single bilayer patches (72 and 288 lipids, respectively), as well as an explicitly multilamellar system consisting of a stack of five 72-lipid bilayers, all replicated in three dimensions by using periodic boundary conditions. The simulation results are compared to X-ray and neutron diffraction data by using a model-free, reciprocal space approach developed recently in our laboratories. Our analysis demonstrates that finite-size effects are negligible in simulations of DOPC bilayers at low hydration, and suggests that refinements are needed in the simulation force fields.

Constant surface tension molecular dynamics simulations of lipid bilayers with trehalose

Surface areas and fluctuations evaluated from 50 ns molecular dynamics simulations of fully hydrated dipalmitoylphosphatidylcholine (DPPC) bilayers in a 1:2 trehalose:lipid ratio carried out at surface tensions 10, 17 and 25 dyn/cm/leaflet are compared with those of pure bilayers under the same conditions. Trehalose increases the surface area, as consistent with the surface tension lowering observed in simulations at constant area. The system bulk elastic modulus K b = 1.5 ± 0.3 × 1010 dyn/cm2. It is independent of bilayer surface area and trehalose content within statistical error. In contrast, the area elastic modulus K a shows a strong area dependence. At 64 Å2/lipid (the experimental surface area), K a = 138 ± 26 dyn/cm for a pure DPPC bilayer and 82 ± 10 dyn/cm for one with trehalose; i.e. trehalose increases fluidity of the bilayer surface at this area per lipid.

Nanopore Formation and Phosphatidylserine Externalization in a Phospholipid Bilayer at High Transmembrane Potential

Atomic-resolution molecular dynamics simulations of lipid bilayers containing 7% phosphatidylserine (PS) on one leaflet are consistent with experimental observations of membrane poration and PS externalization in living cells exposed to nanosecond, megavolt-per-meter electric pulses. Nanometer-diameter aqueous pores develop within nanoseconds after application of an electric field of 450 mV/nm, and electrophoretic transport of the anionic PS headgroup along the newly constructed hydrophilic pore surface commences even while pore formation is still in progress.

Self-consistent mean-field model based on molecular dynamics: application to lipid-cholesterol bilayers.

We have developed a dynamic self-consistent mean-field model, based on molecular-dynamics simulations, to study lipid-cholesterol bilayers. In this model the lipid bilayer is represented as a two-dimensional lattice field in the lipid chain order parameters, while cholesterol molecules are represented by hard rods. The motion of rods in the system is continuous and is not confined to lattice cells. The statistical mechanics of chain ordering is described by a mean field derived from an extension of a model due to Marcelja. The time evolution of the system is governed by stochastic equations. The ensemble of chain configurations required in partition sums, and the energies of interaction, are taken from atomistic level molecular-dynamics simulations of lipid bilayers. The model allows us to simulate systems 500 nm in lateral size for 20 micros time scales, or greater. We have applied the model to dipalmitoyl-phosphatidylcholine-cholesterol (Chol) bilayers at 50 degrees C for Chol concentrations between 2% and 33%. At low concentrations of Chol (2%-4%), the model predicts the formation of isolated clusters of Chol surrounded by relatively ordered lipid chains, randomly dispersed in the disordered bilayer. With increasing Chol composition, regions of Chol-induced order begin to overlap. Starting from about 11% Chol this ordering effect becomes system wide and regions unaffected by Chol are no longer detectable. From the analysis of properties of the model we conclude that the change in lipid chain order with increasing Chol concentration is continuous over the 20-mus scale of the simulations. We also conclude that at 50 degrees C no large-scale Chol-rich and Chol-depleted coexisting phase-separated regions form at any concentration. At no point in any of the simulations do we observe a higher degree of lateral organization, such as Chol-based superlattice structures.