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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.

We introduce a new force field (43A1-S3) for simulation of membranes by the Gromacs simulation package. Construction of the force fields is by standard methods of electronic structure computations for bond parameters and charge distribution and specific volumes and heats of vaporization for small-molecule components of the larger lipid molecules for van der Waals parameters. Some parameters from the earlier 43A1 force field are found to be correct in the context of these calculations, while others are modified. The validity of the force fields is demonstrated by correct replication of X-ray form factors and NMR order parameters over a wide range of membrane compositions in semi-isotropic NTP 1 atm simulations. 43-A1-S3 compares favorably with other force fields used in conjunction with the Gromacs simulation package with respect to the breadth of phenomena that it accurately reproduces.

Experimental evidence indicates that, under some circumstances, “surrogate” molecules may play the same role as cholesterol in ordering membrane lipids. The simplest molecule in this class is Ceramide. In this article, we describe atomic-level molecular dynamics simulations designed to shed light on this phenomenon. We run simulations of hydrated phosphoryl-oleoyl phosphatidylcholine (POPC) bilayers containing cholesterol, and containing ceramide, in concentrations ranging from 5% to 33%. We also perform a simulation of a pure POPC bilayer to verify the simulation force fields against experimental structural data for POPC. Our simulation data are in good agreement with experimental data for the partial molecular volumes, areas, form factors, and order parameters. These simulations suggest that ceramide and cholesterol have a very similar effect on the POPC bilayer, although ceramide is less effective in inducing order in the bilayer compared with cholesterol at the same concentrations.

A pathological feature of Alzheimer's disease (AD) is an area-specific neuronal loss that may be caused by excitotoxicity-related synaptic dysfunction. Relative expression levels of synaptopbysin, dynamin I, complexins I and II, N-cadherin, and alpha CaMKII were analysed in human brain tissue from AD cases and controls in hippocampus, and inferior temporal and occipital cortices. Synaptophysin and dynamin I are presynaptic terminal proteins not specific to any neurotransmitter system whereas complexin II, N-cadherin, and alpha CaMKII are specific for excitatory synapses. Complexin I is a presynaptic protein localised to inhibitory synapses. There were no significant differences in synaptophysin, dynamin I, N-cadherin, or alpha CaMKII protein levels between AD cases and controls. The complexin proteins were both markedly lower in AD cases than in controls (P < 0.01). Cases were also categorised by APOE genotype. Averaged across areas there was a 36% lowering of presynaptic proteins in AD cases carrying at least one epsilon 4 allele compared with in AD cases lacking the epsilon 4 allele. We infer that synaptic protein level is not indicative of neuronal loss, but the synaptic dysfunction may result from the marked relative loss of the complexins in AD, and lower levels of presynaptic proteins in AD cases with the APOE epsilon 4 allele. (c) 2006 Elsevier Ltd. All rights reserved.

It is known from experimental studies that lipid bilayers composed of unsaturated phospholipids, sphingomyelin, and cholesterol contain microdomains rich in sphingomyelin and cholesterol. These domains are similar to “rafts” isolated from cell membranes, although the latter are much smaller in lateral size. Such domain formation can be a result of very specific and subtle lipid-lipid interactions. To identify and study these interactions, we have performed two molecular dynamics simulations, of 200-ns duration, of dioleylphosphatidylcholine (DOPC), sphingomyelin (SM), and cholesterol (Chol) systems, a 1:1:1 mixture of DOPC/SM/Chol, and a 1:1 mixture of DOPC/SM. The simulations show initial stages of the onset of spontaneous phase-separated domains in the systems. On the simulation timescale cholesterol favors a position at the interface between the ordered SM region and the disordered DOPC region in the ternary system and accelerates the process of domain formation. We find that the smooth α-face of Chol preferentially packs next to SM molecules. Based on a comparative analysis of interaction energies, we find that Chol molecules do not show a preference for SM or DOPC. We conclude that Chol molecules assist in the process of domain formation and the process is driven by entropic factors rather than differences in interaction energies.

The displacement of Na+-dependent D-[H-3]aspartate binding by unlabeled D-aspartate or the inhibitors DL-threo-beta-hydroxyaspartate, L-cysteate, L-glutamate, dihydrokainate, DL-alpha-aminoadipate, alpha-methyl-DL-gIutamate, and 1-aminocyclobutane-cis-1,3-dicarboxylate was used to characterize the high-affinity glutamate/aspartate uptake site in human cerebral cortex. Synaptosomal membranes were prepared from tissue obtained at autopsy from nondemented control, Alzheimer's disease (AD), and diffuse Lewy body disease (DLBD) cases, Areas that are damaged in AD (midtemporal, frontal, caudal cingulate, and hippocampal cortices) were compared with those that are spared (occipital and motor cortices), Profiles of the affinities (K-a values) of the ligands showed that areas spared from damage in AD cases differed significantly from equivalent areas in control (p < 0.001) and DLBD (p < 0.001) cases and also from areas susceptible to damage in the same AD cases (p < 0.001). Areas susceptible to damage in AD showed comparable profiles across the three case groups (p = 0.980). The glutamate/aspartate uptake site may be regionally variant in AD cases, and this may underlie local excitotoxicity, D-[H-3]Aspartate binding site density was significantly lower in both dementia groups (control vs, AD, p ( 0.001; control vs. DLBD, p = 0.009; but AD vs, DLBD, p = 0.528); within-group differences were not significant (control, p = 0.874; AD, p = 0.285; DLBD, p = 0.741).

We examine the effects of cholesterol (Chol) on the mechanical properties of membranes consisting of 16:0/18:1 POPC lipid and of lipids with conjugated linoleic acid (CLA), cis-9/trans-11 CLA (C9T11) and trans-10/cis-12 CLA (T10C12). Atomistic molecular dynamics (MD) simulations of POPC–Chol and CLA-Chol mixtures at various Chol concentrations are employed within a recently developed and validated computational methodology (Khelashvili et al., 2013) that calculates from MD trajectories the bending rigidity (KC) for these systems. We have found that the addition of 30% Chol stiffens POPC lipid membranes much more significantly (2.3-fold) than it does C9T11 (1.5-fold) or T10C12 (1.75-fold) lipid bilayers. Extensive comparative structural analysis of the simulated mixtures supports a molecular mechanism for the differential effects of cholesterol, whereby the sterol molecules tilt more significantly in CLA membranes where they also insert deeper inside the hydrocarbon core. The observed distinct arrangement of Chol molecules in CLA and POPC bilayers, in turn, is dictated by the interplay between the specific location of the trans double bond in the two CLA lipid isomers and the preferential interaction of the rigid Chol ring with the saturated segments of the lipid tails. The simulations and analysis described in this paper provide novel insights into the specific modes of molecular interaction in bilayers composed of mixtures of Chol and unsaturated lipids that drive emergent macroscopic properties, such as the membrane's bending modulus.

We present results of off-lattice kinetic Monte Carlo simulations of early stages of low-pressure diamond film growth from a C[111] substrate via methyl radical and hydrogen vapor deposition. Interactions are governed by a semiempirical interatomic potential energy function. Rates for surface chemisorption and desorption of hydrogen and chemisorption of methyl radical that have been calculated by Raff and co-workers are used to assign real time to the Monte Carlo steps. The rate-determining step is the deposition or attempted deposition of methyl radical. Between ${\mathrm{CH}}_{3}$ surface events, the surface is relaxed by standard Monte Carlo methods. During the relaxation process C-C bonds may form and break, and surface diffusion occurs. We study the rate of formation of pair bonds and larger clusters of chemisorbed carbon over a 20-ms simulation, during which the initial surface becomes covered and small diamond ledges begin to form. This rate of growth is in accord with observed rates for diamond film growth from methyl radical. \textcopyright{} 1996 The American Physical Society.

In this paper we report on the molecular dynamics simulation of a fluid phase hydrated dimyristoylphosphatidylcholine bilayer. The initial configuration of the lipid was the x-ray crystal structure. A distinctive feature of this simulation is that, upon heating the system, the fluid phase emerged from parameters, initial conditions, and boundary conditions determined independently of the collective properties of the fluid phase. The initial conditions did not include chain disorder characteristic of the fluid phase. The partial charges on the lipids were determined by ab initio self-consistent field calculations and required no adjustment to produce a fluid phase. The boundary conditions were constant pressure and temperature. Thus the membrane was not explicitly required to assume an area/phospholipid molecule thought to be characteristic of the fluid phase, as is the case in constant volume simulations. Normal to the membrane plane, the pressure was 1 atmosphere, corresponding to the normal laboratory situation. Parallel to the membrane plane a negative pressure of -100 atmospheres was applied, derived from the measured surface tension of a monolayer at an air-water interface. The measured features of the computed membrane are generally in close agreement with experiment. Our results confirm the concept that, for appropriately matched temperature and surface pressure, a monolayer is a close approximation to one-half of a bilayer. Our results suggest that the surface area per phospholipid molecule for fluid phosphatidylcholine bilayer membranes is smaller than has generally been assumed in computational studies at constant volume. Our results confirm that the basis of the measured dipole potential is primarily water orientations and also suggest the presence of potential barriers for the movement of positive charges across the water-headgroup interfacial region of the phospholipid.

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.

The connection between membrane inhomogeneity and the structural basis of lipid rafts has sparked interest in the lateral organization of model lipid bilayers of two and three components. In an effort to investigate anisotropic lipid distribution in mixed bilayers, a self-consistent mean-field theoretical model is applied to palmitoyloleoylphosphatidylcholine (POPC)--palmitoyl sphingomyelin (PSM)--cholesterol mixtures. The compositional dependence of lateral organization in these mixtures is mapped onto a ternary plot. The model utilizes molecular dynamics simulations to estimate interaction parameters and to construct chain conformation libraries. We find that at some concentration ratios the bilayers separate spatially into regions of higher and lower chain order coinciding with areas enriched with PSM and POPC, respectively. To examine the effect of the asymmetric chain structure of POPC on bilayer lateral inhomogeneity, we consider POPC-lipid interactions with and without angular dependence. Results are compared with experimental data and with results from a similar model for mixtures of dioleoylphosphatidylcholine, steroyl sphingomyelin, and cholesterol.

The ripple, or Pβ′ phase of lipid bilayers, which occurs in bimolecular layers of certain phospholipid molecules, exhibits long range periodic intermolecular correlations. These correlations manifest themselves in the form of periodic undulations, or “ripples” in the topography of the layer. In this paper we review theoretical models for this phase.

The fundamental role of cholesterol in the regulation of eukaryotic membrane structure is well-established. However the manner in which atomic level interactions between cholesterol and lipids, with varying degrees of chain unsaturation and polar groups, affect the overall structure and organization of the bilayer is only beginning to be understood. In this paper we describe a series of Molecular Dynamics simulations designed to provide new insights into lipid-cholesterol interactions as a function of chain unsaturation. We have run simulations of varying concentrations of cholesterol in dipalmitoyl phosphatidylcholine (DPPC), palmitoyl-oleyol phosphatidylcholine (POPC), and dioleyol phosphatidylcholine (DOPC) bilayers. Structural analysis of the simulations reveals both atomistic and systemic details of the interactions and are presented here. In particular, we find that the minimum partial molecular area of cholesterol occurs in POPC-Chol mixtures implying the most favorable packing. Physically, this appears to be related to the fact that the two faces of the cholesterol molecule are different from each other and that the steric cross section of cholesterol molecules drops sharply near the small chain tails.

Modeling membranes is not just modeling another kind of macromolecule, but modeling an entire environment for a large class of biomolecular processes. Membrane modeling poses quite a different set of technical problems and scientific isues from modeling proteins. This paper reviews some of these issues and suggests approaches that seem promising for resolving them based on work in our laboratories and that of others.

We present results of a kinetic Monte Carlo simulation of low-pressure diamond film growth from a C[111] substrate via acetylene and hydrogen vapor deposition. Interactions are governed by a semiempirical interatomic potential-energy function. We find that acetylene binding to a clean C[111] surface is favored in this Monte Carlo process, but adsorption of a second ${\mathrm{C}}_{2}$${\mathrm{H}}_{2}$ is not likely until the neighborhood around the site for the second-layer adsorption contains a sufficient number of first-layer adsorbed molecules. This property of the potential energy is responsible for layer-by-layer growth of the film. We also find that the simulated surface is somewhat rougher than diamond surfaces studied by atomic force microscopy. This suggests a need to include the methyl radical in future simulation models.

Traditional methods of bilayer simulation at an atomistic level fail to capture length and time scales of biological interest. For example, the formation of lipid rafts in ternary mixtures is not observable with Molecular Dynamics (MD) simulations. To address this fundamental problem we have developed a coarse-grained model to simulate lipid bilayers based on self-consistent mean-field theory (SCMFT) that uses MD trajectories to extract simulation parameters, and a library of chain states that is used for statistical mechanical calculations. We have applied this model to two ternary mixtures: DOPC, SM and Cholesterol and POPC, SM and cholesterol. The thermodynamic behavior of these two systems is of interest because they are known from experiment to exhibit coexisting regions of lipid order and disorder, related to lipid rafts, at certain temperatures and concentrations. In this poster we describe predictions of the SCMFT model for both ternary mixtures, over a range of mixture concentrations, and over microsecond time scales. The existence of the single double bond in POPC influences packing among neighboring lipids differently from two double bonds of DOPC, and this has an effect on the system-wide level of lateral organization. The two systems are compared with experiments conducted with these mixtures.

The Monte Carlo method has been employed to study the equilibrium properties of a planar array of hydrocarbon chains interacting with a cholesterol molecule. The chains are arranged to model one monolayer of a lipid bilayer and within this monolayer are allowed to move laterally and change conformations by gauche rotations. In the simulation cell there are 90 lipid chains and a single cholesterol molecule. Periodic boundary conditions are imposed upon the cell. The primary results of the calculations are order parameter profiles for the C-C bonds. These are calculated for (i) all chains, (ii) the 6 chains which are nearest neighbors to the cholesterol, and (iii) the 12 chains which are next-nearest neighbors to the cholesterol. Calculations are carried out for C-14, C-16, and C-18 chains. The results show that cholesterol strongly affects the upper portions of the chains, leaving them less able to change conformations. For C-16 and C-18 chains, the chain termini of the cholesterol neighbors are more disordered than the bulk chain termini. The magnitude of the effect depends strongly on the chain length. The results suggest that the changes in the lipid phase transition caused by cholesterol are a consequence of each cholesterol hindering the rotameric freedom of five to seven lipid chains.

The validity of the silicon displacement cross section, D(E), was investigated by simultaneous measurements of neutron spectra phi(E) and of the accumulated damage D = Kphi induced in 2N2222A transistors. The measured values of phi(E) were folded in with D(E) to obtain phi/sub eq/, the l-MeV equivalent fluence for damage to silicon, and the ratios D/phi/sub eq/ = K were obtained for diverse shapes of phi(E) to determine the stability of K to phi(E) variations. The value of K was seen to be constant (within 4 to 5%, 1sigma) within roughly the same standard deviation as the D = Kphi measurements for two modified reactor spectra that varied by as much as 1000% above a few MeV when normalized at the 0.2-MeV threshold of D(E). This helps substantiate the validity of D(E) in characterizing diverse neutron fields for radiation damage of a practical silicon transistor. Earlier studies with large-volume silicon diodes, for monoenergetic neutrons of 0.7 to 14 MeV, tend to corroborate the D(E) validity for transistors over this energy range. These results attest to the shape in terms of gross structure of D(E), which is governed by the accuracy of the ENDF/B-IV neutron cross-section evaluation used and of themore » Robinson functional representation of the Lindhard factor for determining the fraction of recoil-atom and charged particle kinetic energy that is available to cause displacements.« less

Biological membranes consist to a large extent of lipid bilayers, some of which exhibit fairly sharp phase transitions near body temperatures. We describe here a model for the main observed phase transition in pure lipid monolayers and bilayers. The model contains approximate treatments of hard−core repulsions and weak attractive forces between molecules. We believe that the model accounts qualitatively for many of the experimental properties that the model accounts qualitatively for many of the experimental properties of of monolayers and bilayers. Improvements which should enhance quantitative agreement are also discussed.

In this paper we describe a Monte Carlo calculation of the surface tension of water at 25 °C. The procedure used involves computing the free energy required to create a surface in a system of 256 water molecules with periodic boundary conditions imposed. In order to optimize computing time we have used a modified version of an umbrella sampling algorithm suggested by Torrie and Valleau. The excess surface free energy is computed in a series of steps, the most important of which consist of incremental calculations in which the interface is gradually created. Our final result is γ=97±6 dynes/cm, larger than the experimental value of 72 dyn/cm. Reasons for the rather large difference are discussed. Our result can be used as a basis for comparison of the surface tension of water/air interfaces with the surface tension of other aqueous interfaces calculated using the same technique.

We have carried out an atomic-level molecular dynamics simulation of a system of nanoscopic size containing a domain of 18:0 sphingomyelin and cholesterol embedded in a fully hydrated dioleylposphatidylcholine (DOPC) bilayer. To analyze the interaction between the domain and the surrounding phospholipid, we calculate order parameters and area per molecule as a function of molecule type and proximity to the domain. We propose an algorithm based on Voronoi tessellation for the calculation of the area per molecule of various constituents in this ternary mixture. The calculated areas per sphingomyelin and cholesterol are in agreement with previous simulations. The simulation reveals that the presence of the liquid-ordered domain changes the packing properties of DOPC bilayer at a distance as large as approximately 8 nm. We calculate electron density profiles and also calculate the difference in the thickness between the domain and the surrounding DOPC bilayer. The calculated difference in thickness is consistent with data obtained in atomic force microscopy experiments.

We present the results of several computer simulations using a model for the head group water interface of a lipid bilayer. Simulations were performed using the Monte Carlo method, enhanced by a ’’half‐umbrella sampling’’ algorithm we developed in an earlier paper. Our results can be used in a comparative way, along with the earlier results for pure water, to estimate the effective dipole moment of a typical phospholipid in a bilayer in excess water.

The Monte Carlo method has been utilized to calculate lipid chain order parameters in model monomolecular layers (half-bilayers) containing several different model polypeptides. The systems all consist of a periodic array of identical cells, each containing 35 hydrocarbon chains and 1 "perturbant" (a small model polypeptide or protein). The lipid chains are each 10 CH2 subunits long, have one end constrained to lie in the bilayer plane, and interact via van der Waals forces between all subunits. The chains also interact with the perturbant via van der Waals forces. With standard Monte Carlo procedures order parameter profiles are calculated for chains that are close to the perturbant and for the nonneighboring chains. In order to examine a wide range of possibilities, several different model polypeptides are considered: (i) a rigid smooth cylinder, (ii) a cylinder with identical side chains at alpha-helical positions, (iii) a cylinder with nonidentical side chains at alpha-helical positions, and (iv) a cylinder identical with (ii) but which only extends about halfway through the monolayer. Although results differ for the different systems studied, in all cases only slight conformational differences between the bulk chains and the chains that are nearest the perturbants are found, and it is not possible to characterize the boundary chains as "more ordered" or "less ordered" than the nonboundary chains.