Simulations Of Lipid Bilayers Research Articles

Molecular Dynamics Comparison of Electroporation in Water-Vacuum-Water and Lipid Bilayer System

A recent study showed that water forms cone-like structures at a vacuum or air interface under a sufficiently high electric field [1]. This protruding water formation may be a key step in the initiation of electroporation of lipid bilayers and cell membranes. In molecular dynamics (MD) simulations of water-vacuum-water (WVW) systems, we observe the intrusion of water into the vacuum region, similar to the pore initiation stage of electropore formation in phospholipid bilayer systems [2]. Pore initialization time in WVW systems is found to decay exponentially with applied electric field, consistent with simulations of lipid bilayers [2]. Pore initialization time in WVW systems also increases exponentially with increasing vacuum gap size. We analyze pore creation, pore annihilation, and pore stabilization. By comparing the evolution of the pore radius in both systems, we can begin to quantify how water and phospholipids each contribute to the formation and stability of lipid nanopores.1. Okuno, Y., Minagawa M., Matsumoto H., and Tanioka A. 2009. Simulation study on the influence of an electric field on water evaporation. J Mol Struct 904:83-90.2. Levine, Z. A., and Vernier, P. T. 2010. Life Cycle of an Electropore: Field-Dependent and Field-Independent Steps in Pore Creation and Annihilation. J Membrane Biol 236:27-36.

GAFFlipid: a General Amber Force Field for the accurate molecular dynamics simulation of phospholipid

Previous attempts to simulate phospholipid bilayers using the General Amber Force Field (GAFF) yielded many bilayer characteristics in agreement with experiment, however when using a tensionless NPT ensemble the bilayer is seen to compress to an undesirable extent resulting in low areas per lipid and high order parameters in comparison to experiment. In this work, the GAFF Lennard-Jones parameters for the simulation of acyl chains are corrected to allow the accurate and stable simulation of pure lipid bilayers. Lipid bilayers comprised of six phospholipid types were simulated for timescales approaching a quarter of a microsecond under tensionless constant pressure conditions using Graphics Processing Units. Structural properties including area per lipid, volume per lipid, bilayer thickness, order parameter and headgroup hydration show favourable agreement with available experimental values. Expanding the system size from 72 to 288 lipids and a more experimentally realistic 2 × 288 lipid bilayer stack induces little change in the observed properties. This preliminary work is intended for combination with the new AMBER Lipid11 modular force field as part of on-going attempts to create a modular phospholipid AMBER force field allowing tensionless NPT simulations of complex lipid bilayers.

Update of the Cholesterol Force Field Parameters in CHARMM

A modification of the CHARMM36 lipid force field (C36) for cholesterol, henceforth, called C36c, is reported. A fused ring compound, decalin, was used to model the steroid section of cholesterol. For decalin, C36 inaccurately predicts the heat of vaporization (~10 kJ/mol) and molar volume (~10 cc/mol), but C36c resulted in near perfect comparison with experiment. MD simulations of decalin and heptane at various compositions were run to estimate the enthalpy and volumes of mixing to compare to experiment for this simple model of cholesterol in a chain environment. Superior estimates for these thermodynamic properties were obtained with C36c versus C36. These new parameters were applied to cholesterol, and quantum mechanical calculations were performed to modify the torsional potential of an acyl chain torsion for cholesterol. This model was tested through simulations of DMPC/10% cholesterol, DMPC/30% cholesterol, and DOPC/10% cholesterol. The C36 and C36c results were similar for surface areas per lipid, deuterium order parameters, electron density profiles, and atomic form factors and generally agree well with experiment. However, C36 and C36c produced slightly different cholesterol angle distributions with C36c adopting a more perpendicular orientation with respect to the bilayer plane. The new parameters in the C36c modification should enable more accurate simulations of lipid bilayers with cholesterol, especially for those interested in the free energy of lipid flip/flop or transfer of phospholipids and/or cholesterol.

Cationic Dimyristoylphosphatidylcholine and Dioleoyloxytrimethylammonium Propane Lipid Bilayers: Atomistic Insight for Structure and Dynamics

We performed atomistic molecular dynamics simulations of lipid bilayers consisting of a mixture of cationic dioleoyloxytrimethylammonium propane (DOTAP) and zwitterionic dimyristoylphosphatidylcholine (DMPC) lipids at different DOTAP fractions. Our primary focus was the specific effects of unsaturated lipid chains on structural and dynamic properties of mixed cationic bilayers. The bilayer area, as well as the ordering of lipid tails, shows a pronounced nonmonotonic behavior when TAP lipid fraction increases. The minimum in area (maximum in ordering) was observed for a bilayer with TAP fraction of 0.4, that is, at lower TAP fractions compared with saturated PC/TAP bilayers. Adding unsaturated DOTAP lipids into DMPC bilayers was found to promote lipid chain interdigitation and to fluidize lipid bilayers, as seen through enhanced lateral lipid diffusion. The speed-up in lateral diffusion at large DOTAP fractions results from increasing area per lipid, whereas at smaller DOTAP concentrations, the competing effect due to lipid-lipid complex formation results in a constant value for diffusion. We also characterize the lipid headgroup orientation and the interactions between DMPC and DOTAP lipids, which were found to form PC-PC and PC-TAP pairs, and the formation of lipid clusters.

Molecular dynamic simulation study of cholesterol and conjugated double bonds in lipid bilayers

Conjugated linoleic acids (CLA) are found naturally in dairy products. Two isomers of CLA, that differ only in the location of cis and trans double bonds, are found to have distinct and different biological effects. The cis 9 trans 11 (C9T11) isomer is believed to have anti-carcinogenic effects, while the trans 10 cis 12 (T10C12) isomer is believed to be associated with anti-obesity effects. In this paper we extend earlier molecular dynamics (MD) simulations of pure CLA–phosphatidylcholine bilayers to investigate the comparative effects of cholesterol on bilayers composed of the two respective isomers. Simulations of phosphatidylcholine lipid bilayers in which the sn-2 chains contained one of the two isomers of CLA were performed in which, for each isomer, the simulated bilayers contained 10% and 30% cholesterol (Chol). From MD trajectories we calculate and compare structural properties of the bilayers, including areas per molecule, thickness of bilayers, tilt angle of cholesterols, order parameter profiles, and one and two-dimensional radial distribution function (RDF), as functions of Chol concentration. While the structural effect of cholesterol is approximately the same for both isomers, we find differences at an atomistic level in order parameter profiles and in two-dimensional radial distribution functions.

Association of Lipidome Remodeling in the Adipocyte Membrane with Acquired Obesity in Humans

Author SummaryObesity is characterized by excess body fat, which is predominantly stored in the adipose tissue. When adipose tissue expands too much it stops storing lipid appropriately. The excess lipid accumulates in organs such as muscle, liver, and pancreas, causing metabolic disease. In this study, we aim to identify factors that cause adipose tissue to malfunction when it reaches its limit of expansion. We performed lipidomic analyses of human adipose tissue in twin pairs discordant for obesity—that is, one of the twins was lean and one was obese—but still metabolically healthy. We identified multiple changes in membrane phospholipids. Using computer modeling, we show that “lean” and “obese” membrane lipid compositions have the same physical properties despite their different compositions. We hypothesize that this represents allostasis—changes in lipid membrane composition in obesity occur to protect the physical properties of the membranes. However, protective changes cannot occur without a cost, and accordingly we demonstrate that switching to the “obese” lipid composition is associated with higher levels of adipose tissue inflammation. In a separate group of metabolically unhealthy obese individuals we investigated how the processes that regulate the “lean” and “obese” lipid profiles are changed. To determine how these lipid membrane changes are regulated we constructed an in silico network model that identified key control points and potential molecular players. We validated this network by performing genetic manipulations in cell models. Therapeutic targeting of this network may open new opportunities for the prevention or treatment of obesity-related metabolic complications.

Interpretation of Fluctuation Spectra in Lipid Bilayer Simulations

Atomic resolution and coarse-grained simulations of dimyristoylphosphatidylcholine lipid bilayers were analyzed for fluctuations perpendicular to the bilayer using a completely Fourier-based method. We find that the fluctuation spectrum of motions perpendicular to the bilayer can be decomposed into just two parts: 1), a pure undulation spectrum proportional to q −4 that dominates in the small- q regime; and 2), a molecular density structure factor contribution that dominates in the large- q regime. There is no need for a term proportional to q −2 that has been postulated for protrusion fluctuations and that appeared to have been necessary to fit the spectrum for intermediate q. We suggest that earlier reports of such a term were due to the artifact of binning and smoothing in real space before obtaining the Fourier spectrum. The observability of an intermediate protrusion regime from the fluctuation spectrum is discussed based on measured and calculated material constants.

Determination of Electron Density Profiles and Area from Simulations of Undulating Membranes

The traditional method for extracting electron density and other transmembrane profiles from molecular dynamics simulations of lipid bilayers fails for large bilayer systems, because it assumes a flat reference surface that does not take into account long wavelength undulations. We have developed what we believe to be a novel set of methods to characterize these undulations and extract the underlying profiles in the large systems. Our approach first obtains an undulation reference surface for each frame in the simulation and subsequently isolates the long-wavelength undulations by filtering out the intrinsic short wavelength modes. We then describe two methods to obtain the appropriate profiles from the undulating reference surface. Most combinations of methods give similar results for the electron density profiles of our simulations of 1024 DMPC lipids. From simulations of smaller systems, we also characterize the finite size effect related to the boundary conditions of the simulation box. In addition, we have developed a set of methods that use the undulation reference surface to determine the true area per lipid which, due to undulations, is larger than the projected area commonly reported from simulations.

Interleaflet Interaction and Asymmetry in Phase Separated Lipid Bilayers: Molecular Dynamics Simulations

In order to investigate experimentally inaccessible, molecular-level detail regarding interleaflet interaction in membranes, we have run an extensive series of coarse-grained molecular dynamics simulations of phase separated lipid bilayers. The simulations are motivated by differences in lipid and cholesterol composition in the inner and outer leaflets of biological membranes. Over the past several years, this phenomenon has inspired a series of experiments in model membrane systems which have explored the effects of lipid compositional asymmetry in the two leaflets. The simulations are directed at understanding one potential consequence of compositional asymmetry, that being regions of bilayers where liquid-ordered (L(o)) domains in one leaflet are opposite liquid-disordered (L(d)) domains in the other leaflet (phase asymmetry). The simulated bilayers are of two sorts: 1) Compositionally symmetric leaflets where each of the two leaflets contains an identical, phase separated (L(o)/L(d)) mixture of cholesterol, saturated and unsaturated phospholipid; and 2) Compositionally asymmetric leaflets, where one leaflet contains a phase separated (L(o)/L(d)) mixture while the other contains only unsaturated lipid, which on its own would be in the L(d) phase. In addition, we have run simulations where the lengths of the saturated lipid chains as well as the mole ratios of the three lipid components are varied. Collectively, we report on three types of interleaflet coupling within a bilayer. First, we show the effects of compositional asymmetry on acyl chain tilt and order, lipid rotational dynamics, and lateral diffusion in regions of leaflets that are opposite L(o) domains. Second, we show substantial effects of compositional asymmetry on local bilayer curvature, with the conclusion that phase separated leaflets resist curvature, while inducing large degrees of curvature in an opposing L(d) leaflet. Finally, in compositionally symmetric, phase separated bilayers, we find phase asymmetry (domain antiregistration) between the two leaflets occurs as a consequence of mismatched acyl chain-lengths in the saturated and unsaturated lipids.

Molecular dynamics simulation of lipid packing and mobility in bilayer membranes

A model of lipid bilayer membrane in water has been developed. Parameters have been selected that allow molecular dynamics simulation of lipid bilayers in the all-atom approximation. The calculated indices of packing and mobility of lipid molecules for the liquid crystalline state of the bilayer agree well with the experimental data. Based on the model of the liquid crystalline state of the membrane, a system in the gel-like state has been constructed. The gel-state model reproduces well the packing of lipids in real bilayers, whereas the mobility of molecules proves to be overestimated.

Atomic view of calcium-induced clustering of phosphatidylserine in mixed lipid bilayers.

Membranes play key regulatory roles in biological processes, with bilayer composition exerting marked effects on binding affinities and catalytic activities of a number of membrane-associated proteins. In particular, proteins involved in diverse processes such as vesicle fusion, intracellular signaling cascades, and blood coagulation interact specifically with anionic lipids such as phosphatidylserine (PS) in the presence of Ca(2+) ions. While Ca(2+) is suspected to induce PS clustering in mixed phospholipid bilayers, the detailed structural effects of this ion on anionic lipids are not established. In this study, combining magic angle spinning (MAS) solid-state NMR (SSNMR) measurements of isotopically labeled serine headgroups in mixed lipid bilayers with molecular dynamics (MD) simulations of PS lipid bilayers in the presence of different counterions, we provide site-resolved insights into the effects of Ca(2+) on the structure and dynamics of lipid bilayers. Ca(2+)-induced conformational changes of PS in mixed bilayers are observed in both liposomes and Nanodiscs, a nanoscale membrane mimetic of bilayer patches. Site-resolved multidimensional correlation SSNMR spectra of bilayers containing (13)C,(15)N-labeled PS demonstrate that Ca(2+) ions promote two major PS headgroup conformations, which are well resolved in two-dimensional (13)C-(13)C, (15)N-(13)C, and (31)P-(13)C spectra. The results of MD simulations performed on PS lipid bilayers in the presence or absence of Ca(2+) provide an atomic view of the conformational effects underlying the observed spectra.

Conjugated double bonds in lipid bilayers: A molecular dynamics simulation study

Conjugated linoleic acids (CLA) are found naturally in dairy products. Two isomers of CLA, that differ only in the location of cis and trans double bonds, are found to have distinct and different biological effects. The cis 9 trans 11 (C9T11) isomer is attributed to have the anti-carcinogenic effects, while the trans 10 cis 12 (T10C12) isomer is believed to be responsible for the anti-obesity effects. Since dietary CLA are incorporated into membrane phospholipids, we have used Molecular Dynamics (MD) simulations to investigate the comparative effects of the two isomers on lipid bilayer structure. Specifically, simulations of phosphatidylcholine lipid bilayers in which the sn-2 chains contained one of the two isomers of CLA were performed. Force field parameters for the torsional potential of double bonds were obtained from ab initio calculations. From the MD trajectories we calculated and compared structural properties of the two lipid bilayers, including areas per molecule, density profiles, thickness of bilayers, tilt angle of tail chains, order parameters profiles, radial distribution function (RDF) and lateral pressure profiles. The main differences found between bilayers of the two CLA isomers, are (1) the order parameter profile for C9T11 has a dip in the middle of sn-2 chain while the profile for T10C12 has a deeper dip close to terminal of sn-2 chain, and (2) the lateral pressure profiles show differences between the two isomers. Our simulation results reveal localized physical structural differences between bilayers of the two CLA isomers that may contribute to different biological effects through differential interactions with membrane proteins or cholesterol.

Molecular Dynamics Simulations of Anionic Lipid Bilayers in Presence of Calcium Ions

The negatively charged phosphatidylserine (PS) lipid molecules contribute up to 17% of the lipid composition in mammalian cell membranes. Experiments have shown that PS lipids, in presence of Ca2+ ions, are involved in a number of membrane-mediated processes such as phase separation, membrane fusion, and protein topological changes.However, although experiments have been performed aimed at understanding the interactions of Ca2+ ions with PS lipids, the detailed mechanism of Ca2+ induced changes in PS-containing membranes is not well established. This is, in part, due to the lack of conformational information at the atomistic level in experimental measurements.Molecular dynamics (MD) simulation is a powerful tool in elucidating phenomena at the molecular level and has been used widely in the field of biophysics. Specifically, several atomistic MD simulation studies have been performed to study the properties of model membranes containing PS in absence and presence of Ca2+ ions. However, it remains challenging to observe changes in membrane structure due to the presence of Ca2+ ions.We are using atomistic and coarse-grained MARTINI simulations of membranes containing PS to study the role of Ca2+ ions in modifying structural and dynamic properties of the membranes.

Molecular Dynamics Simulation of Solid-Supported Lipid Bilayers

Systems consisting of a solvated bilayer adsorbed on a solid surface and exposed to an air/vacuum interface occur in many experimental settings. Here, we investigated the effects of implementing different electrostatic boundary conditions in molecular dynamics simulations of a quartz-supported hydrated lipid bilayer exposed to vacuum. Since these interfacial systems have a net polarization, implementing the standard Ewald summation with the conducting boundary condition for the electrostatic long-range interactions introduced an artificial periodicity in the out-of-plane dimension. In particular, abnormal orientational polarizations of water were observed with the conducting boundary condition. Implementing the Ewald summation technique with the planar vacuum boundary condition and calculating electrostatic properties compatible with the implemented electrostatic boundary condition removed these inconsistencies. This formulation is generally applicable to similar interfacial systems in bulk solution.

Recent development in computer simulations of lipid bilayers

Rapid development of computer power during the last decade has made molecular simulations of lipid bilayers feasible for many research groups, which, together with the growing general interest in investigations of these very important biological systems has lead to tremendous increase of the number of research on the computational modeling of lipid bilayers. In this review, we give account of the recent progress in computer simulations of lipid bilayers covering mainly the period of the last 5 years, and covering several selected subjects: development of the force fields for lipid bilayer simulations, studies of the role of lipid unsaturation, the effect of cholesterol and other inclusions on properties of the bilayer, and use of coarse-grained models.

Nanoscale carbon particles and the stability of lipid bilayers

The transfer of various nano-scale fullerenes into lipid bilayers has been studied using all-atom (AA) and coarse-grained (CG) molecular dynamics (MD) simulations. The free energy change, when C60, C180, and C540 fullerenes are transferred from water to the interior of a lipid [dioleoylphosphatidylcholine (DOPC)] bilayer, has been calculated. Upon entering the lipid bilayer, the largest (2.4 nm diameter) fullerene causes local distortions in the bilayer surface, which were previously observed in carbon nanotube simulations. These local distortions, however, do not lead to any free energy barriers to bilayer entry. The free energy profiles confirm spontaneous absorption of all three fullerenes. Qualitative agreement was observed when comparing fullerene partitioning in water/bilayer systems to water–hexane systems. In contrast to these nonspecific single fullerene properties, extensive CG-MD simulations of fullerene rich lipid bilayers reveal substantial impact of fullerene-size on the bilayer stability. While previous CG-MD simulations indicated that bilayer bound C60 aggregates have little effect on the bilayer structure, the present MD simulations indicate that C540 aggregation has drastic effects. Specifically, the observed destabilization likely has implications for understanding the cytotoxic mechanisms of nano-carbon particles upon uptake by biological cells.

Stretched exponential dynamics in lipid bilayer simulations

The decay of fluctuations in fluid biomembranes is strongly stretched and nonexponential on nanometer lengthscales. We report on calculations of structural correlation functions for lipid bilayer membranes from atomistic and coarse-grained molecular dynamics simulations. The time scales extend up to microseconds, whereas the linear size of the largest systems is around 50 nm. Thus, we can cover the equilibrium dynamics of wave vectors over two orders of magnitude (0.2-20 nm(-1)). The time correlations observed in the simulations are best described by stretched exponential functions, with exponents of 0.45 for the atomistic and 0.60 for the coarse-grained model. Area number density fluctuations, thickness fluctuations, and undulations behave dynamically in a similar way and have almost exactly the same dynamics for wavelengths below 3 nm, indicating that in this regime undulations and thickness fluctuations are governed by in-plane density fluctuations. The out-of-plane height fluctuations are apparent only at the longest wavelengths accessible in the simulations (above 6 nm). The effective correlation times of the stretched exponentials vary strongly with the wave vector. The variation fits inverse power-laws that change with wavelength. The exponent is 3 for wavelengths smaller than about 1.25 nm and switches to 1 above this. There are indications for a switch to still another exponent, 2, for wavelengths above 20 nm. Compared to neutron spin-echo (NSE) experiments, the simulation data indicate a faster relaxation in the hydrodynamic limit, although an extrapolation of NSE data, as well as inelastic neutron scattering data, is in agreement with our data at larger wave vectors.

Communications: Self-energy and corresponding virial contribution of electrostatic interactions in dissipative particle dynamics: Simulations of cationic lipid bilayers

General expressions of self-energy and corresponding virial terms for electrostatic interactions in dissipative particle dynamics simulations are derived in this article. In the lattice-sum electrostatics, we found the essential process is to solve the electric field equation of each individual point charge. Strong inward pressure caused by the self-energy is eliminated by subtracting the corresponding virial from the total virial. The resulting method is tested by simulating cationic lipid bilayers in constant pressure ensemble.

Calgary Lipids: A Lipid Force Field for Molecular Simulations

Lipid bilayers are fundamental components of biological membranes. The most biologically relevant state of lipid bilayers is the fully hydrated fluid phase (fluid-disordered or liquid-ordered). Due to their fluidity, it is not possible to obtain experimentally atomic level structures of single bilayers. Computer simulations have been widely used to study lipid bilayers, providing detailed structural information that can aid the interpretation of experimental results. A large body of literature is available on simulations of lipid bilayers, but different studies used different simulation conditions and different force fields, which makes it difficult to compare results for different lipids.We present here a new united-atoms force fields for lipids, compatible with common protein force fields. Partial charges and dihedral angle profiles were derived from quantum mechanics calculations on lipid fragments, while Lennard-Jones parameters were tuned by fitting thermodynamic data for simple molecular building blocks. We built a library of structures of 60 different lipid bilayers, generated using molecular dynamics simulations in identical conditions. The library provides comparable structural data for bilayers with 4 different head groups and 15 pairs of acyl chains, including the most common lipid molecules. Structural parameters (such as the area per lipid and the electron density profiles) as well as dynamic properties (diffusion coefficients, deuterium order parameters) have been calculated for each bilayer, allowing for a systematic analysis of the effect of chain length, chain unsaturation and the chemical nature of the head group.

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.