[Temperature dependence of conformational properties of natural lipid oligomer chains: computer simulation].

The conformational properties of several oligomeric chain molecules at T = 278 and T = 403 K have been studied using Monte Carlo computer simulations. Hydrocarbon oligomers with methylene-interrupted cis double bonds in the main chain were considered. These oligomers are typical constituents of natural lipid molecules. The characteristics of the shape of C-H and C-C bond orientation distribution functions with respect to the principal axis of inertia of the chains and their temperature dependences were studied. It was found that the temperature sensitivity of not only the common geometric characteristics of the polyunsaturated chain is significantly reduced compared with the saturated one, but also that of local characteristics, i. e., the shape of each bond orientation distribution function of the polyunsaturated chain. The relationship between the properties of lipid polyunsaturated hydrocarbon chains and their functions in natural membrane systems, in particular their possible role in the stabilization or optimization of lipid-protein interactions, was discussed.

[Effect of cholesterol on the bond ordering in hydrated unsaturated lipid bilayers].

Molecular dynamics computer simulations of hydrated bilayers of unsaturated phosphatidylcholines in which double bonds are in the states: 18:0/18:1(n-9)cis (PC), 18:0/18:2(n-6)cis (PC), 18:0/18:3(n-3)cis (PC), 18:0/20:4(n-6)cis (PC), and 18:0/22:6(n-3)cis in the presence of cholesterol (40 mol%) and its absence have been performed. The simulation have been performed at 303 K and 1 atm, under the conditions corresponding to the experimentally observed liquid-crystalline state of the bilayer from phosphatidylcholine. The C-C and C-H bond order parameter profiles with respect to the bilayer normal and the C-C bond orientation distribution functions have been calculated. The widths of the functions and positions of their maxima have been determined. The dependence of these characteristics on the type of the bond, the degree of unsaturation of the chain, the presence of cholesterol in the bilayer, and the bond order parameters have been analyzed.

[Effect of cholesterol on the structure and dynamic properties of unsaturated phospholipid bilayers].

Molecular dynamics (MD) computer simulations of five different hydrated unsaturated phosphatidylcholine lipid bilayers built up by 18:0/18:1(n-9)cis PC, 18:0/18:2(n-6)cis PC, 18:0/18:3(n-3)cis PC, 18:0/20:4(n-6)cis PC, and 18:0/22:6(n-3)cis PC molecules with 40 mol% cholesterol, and the same five pure phosphatidylcholine bilayers have been performed at 303 K. The simulation box of a lipid bilayer contained 96 phosphatidylcholines, 64 cholesterols, and 3840 water molecules (48 phosphatidylcholine molecules and 32 cholesterols per layer and 24 water molecules per phospholipid or cholesterol in each case). The lateral self-diffusion coefficients of the lipids in these systems and mass density profiles with respect to the bilayer normal have been analyzed. It has been found that the lateral diffusion coefficients of phosphatidylcholine molecules increase with increasing number of double bonds in one of the lipid chains, both in pure bilayers and in bilayers with cholesterol. It has been found as well that the lateral diffusion coefficient of phosphatidylcholine molecules of a lipid bilayer with 40 mol% cholesterol is smaller than that for the corresponding pure phosphatidylcholine bilayer.

Interaction of cholesterol-like molecules in polyunsaturated phosphatidylcholine lipid bilayers as revealed by a self-consistent field theory.

Cholesterol is one of the most abundant components in biological membranes. In this paper we apply a detailed state-of-the-art self-consistent field (SCF) theory to predict the influence of cholesterol-look-alikes in the bilayer composed of 1-stearoyl-2-docosahexaenoyl-sn-glycero-3-phosphatidylcholine (18:022:6omega3cis PC) lipids with a polyunsaturated 22:6 and a fully saturated 18:0 tail. The cholesterol-like molecule is composed of a hydroxyl group, a rigid chain fragment with length n segments and a branched semiflexible moiety with methylene side groups. We vary both the length of the rigid fragment in the cholesterol-look-alikes and their mole fraction in the tensionless bilayers. We find that these additives significantly increase the order of the saturated tails, but influence the conformational properties of the unsaturated tail much less. With increasing loading the bilayer thickness and the area available per PC head group increase. The hydroxyl group anchors close to the membrane-water interface, but with increasing loading the distribution of this polar group widens. The orientational order of the rigid part is high and we conclude that the cholesterol has significant mobility in the normal direction in the hydrophobic region of the bilayer indicating that one singly hydroxyl group is giving only a weak anchoring to the water-interface. Cholesterol-look-alikes increase the fluctuation of the tail ends and decrease the interdigitation of the tails. Several of our predictions correspond to molecular dynamics (MD) simulation results, but there are also important differences. Most notably the cholesterol-look-alikes can visit the membrane symmetry-plane more easily in SCF than in MD. Possible reasons for this are discussed.

Computer simulation study of intermolecular voids in unsaturated phosphatidylcholine lipid bilayers.

Computer simulation of the liquid crystalline phase of five different hydrated unsaturated phosphadidylcholine (PC) lipid bilayers, i.e., membranes built up by 18:0/18:1omega9cis PC, 18:0/18:2omega6cis PC, 18:0/18:3omega3cis PC, 18:0/20:4omega6cis PC, and 18:0/22:6omega3cis PC molecules have been performed on the isothermal-isobaric ensemble at 1 atm and 303 K. (The notation n:domegapcis specifies the lipid tails: n refers to the total number of carbon atoms in the chain, d is the number of the methylene-interrupted double bonds, p denotes the number of carbons between the chain terminal CH(3) group and the nearest double bond, and cis refers to the conformation around the double bonds.) The characteristics of the free volume in these systems have been analyzed by means of a generalized version of the Voronoi-Delaunay method [M. G. Alinchenko et al., J. Phys. Chem. B 108, 19056 (2004)]. As a reference system, the hydrated bilayer of the saturated 14:014:0 PC molecules (dimyristoylphosphatidylcholine) has also been analyzed. It has been found that the profiles of the fraction of the free volume across the membrane exhibit a rather complex pattern. This fine structure of the free volume fraction profiles can be interpreted by dividing the membrane into three separate major zones (i.e., zones of the aqueous, polar, and apolar parts of the membrane) and defining five subzones within these zones according to the average position of various atomic groups in the membrane. The fraction of the free volume in the middle of the membrane is found to increase with increasing unsaturation of the sn-2 chain of the lipid molecule. This is due to the fact that with increasing number of methylene-interrupted double bonds the lipid tails become more flexible, and hence they do not extend to the middle of the membrane. It is found that there are no broad enough preformed channels in the bilayers through which small penetrants, such as water molecules, can readily go through; however, the existing channels can largely facilitate the permeation of these molecules.

Molecular dynamics simulations of hydrated unsaturated lipid bilayers in the liquid-crystal phase and comparison to self-consistent field modeling.

Molecular dynamics simulations, using the collision dynamics method, were carried out for hydrated bilayers of 1-stearoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (18:0/18:1 omega 9cis PC, SOPC) and 1-stearoyl-2-docosahexaenoyl-sn-glycero-3-phosphatidylcholine (18:0/22:6 omega 3cis PC, SDPC). The simulation cells of the two bilayers consisted of 96 SOPC (or SDPC) molecules and 2304 water molecules: 48 lipid molecules per layer and 24 H2O molecules per lipid. The water was modeled by explicit TIP3P water molecules. The C-H bond-order-parameter -S(CH) profiles of the hydrocarbon tails, the bond orientation distribution functions and the root-mean-square values of the positional fluctuations of the lipid chain carbons were calculated. Simulation results are compared to the available experimental data and to other computer investigations of these lipid molecules. Several results of molecular-level self-consistent field calculations of these bilayers are also presented. Both theoretical methods reveal the same main characteristic features of the order-parameter profiles for the given bilayers. Some aspects of the physical properties of unsaturated lipids and their biological significance are discussed.

Self-consistent-field modeling of hydrated unsaturated lipid bilayers in the liquid-crystal phase and comparison to molecular dynamics simulations.

A molecular-level self-consistent-field (SCF) theory is applied to model the lipid bilayer structures composed of 1-stearoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (18:0/18:1 omega 9cis PC) and 1-stearoyl-2-docosahexaenoyl-sn-glycero-3-phosphatidylcholine (18:0/22:6 omega 3cis PC). As compared to earlier attempts to model (saturated) PC membranes several additional features are implemented: (i) A water model is used which correctly leads to low water concentration in the bilayers. (ii) Free volume is allowed for, which is important to obtain bilayers in the fluid state. (iii) A polarization term is included in the segment potentials; this new feature corrects for a minor thermodynamic inconsistency present in (all) earlier results for charged bilayers. (iv) The CH3 groups in the lipid molecules are assumed to have twice the volume of a CH2 group; this leads to stable noninterdigitated bilayers. (v) A cis double bond is simulated by forcing gauche conformations along the sn-2 acyl chain. Results of an all-atom molecular dynamics (MD) simulation, using the collision dynamics method, on the same system are presented. Both SCF and MD prove, in accordance with experimental facts, that acyl unsaturation effectively reduces the length of the chain which counteracts interdigitation. It is also found that the phosphatidylcholine head group is lying almost flat on the membrane surface and the water penetrates into the bilayer upto the glycerol backbone units. From the SCF results it further followed that the free volume is not exactly evenly distributed over the bilayer. There is a small increase in free volume in the center of the bilayer as well as in the glycerol backbone region.

[Computer study of intramolecular ordering in octadecatriene chains with cis-double bonds]. / Komp'iuternoe issledovanie vnutrimolekuliarnoi uporiadochennosti v oktadekatrienovykh tsepiakh s tsis-dvoinymi sviaziami.

Computer simulations of isolated unperturbed hydrocarbon molecules of C18:3 with methylene-interrupted cis double bonds were carried out using the Monte Carlo method based on the continuum model. A molecule-fixed coordinate system (with the axes along the principal axes of inertia of each molecule conformation) was used. The orientation distribution functions rho and order parameters S for C-H and C-C bonds relative to the maximum molecule span axis were calculated. It was shown that the widths of functions rho (factor of bond "fluctuations") are dependent on the chemical structure and position of the segment, fluctuations increase from the centre of the chain towards the terminals, all things being equal. The orientation distributions rho of C-H bonds flanking the double bond are the most narrow, the functions rho of CH2-groups located between two double bonds are the widest. It turned out that order parameter -SCH profiles of isolated chains of C18:3 include both the positive and negative values. The parameter SCC odd-even effect in unsaturated molecules of such structure changes the sign between double bonds.

[Polyunsaturated hydrocarbon chains: computer study of the characteristics of intramolecular ordering of chains]. / Polinenasyshchennye uglevodorodnye tsepi: komp'iuternoe issledovanie kharakteristik vnutrimolekuliarnoi uporiadochennosti sviazei.

The conformational properties of isolated unbranched hydrocarbon polyunsaturated molecules of cis-C18:4 and cis-C18:5 under theta-conditions (T = 298 K) were studied using Monte Carlo simulations. The conformations were generated by a computer (the continuum model was used; the energy of nonbonded interactions and torsion and electrostatic terms were taken into account). A molecule-fixed coordinate system with the axes along inertia tensor eigenvectors of each molecule conformation (principal axes of inertia) were used for the calculations. C-H and C-C bond orientation distribution functions rho and ordering parameters S with respect to the maximum molecule span axis were calculated. It was shown that the presence of five methylene-interrupted cis double bonds in C18 chain has a maximum effect on the intramolecular ordering properties of the molecule. The widths of function rho CH for pentaenes differed significantly from those of other C18-chains: the widths of function rho for all CH2-groups were nearly twice as large as that for C-H-bonds flanking the double bonds C=C, and roughly constant along the chain sequence. The mean magnitudes of magnitudes of SCH in the molecule decreased when unsaturation increased.

A computer investigation of intramolecular bond ordering: unsaturated chains of natural lipids.

Computer simulations (by the Monte Carlo method) of unperturbed linear hydrocarbon chains of 18-22 carbon atoms with methylene-interrupted cis-double bonds (18:0, 20:0, 22:0, 18:1delta11cis, 18:2delta9, 12cis, 18:3delta9, 12, 15cis, 20:3delta5, 8, 11cis, 20:4delta5, 8, 11, 14cis, 20:5delta5, 8, 11, 14, 17cis, 22:6delta4, 7, 10, 13, 16, 19cis), typical components of natural lipids, at a temperature of 298 K have been carried out. The conformations generated with continuous variation of all single C-C bond rotation angles within the (0, 360 degrees) range have been considered. The energy of nonbonded interactions and torsion and electrostatic terms have been taken into account. The intramolecular bond order parameters S(CC) and S(CH) about the axes along inertia tensor eigenvectors and bond orientation distributions rho(theta) with respect to the maximum molecule span axis (theta is the angle between the bond and the axis) have been calculated. The relation of the bond orientation distributions rho(theta) to the order parameters S are analyzed in terms of angles thetamax (a "geometric" factor, rho(thetamax) = max) and widths deltatheta of the distributions (factor of "fluctuations"). The results indicate that fluctuation factors depend on both the segment chemical structure and location in the chain; fluctuations increase from the centre of the chain towards the terminals, all things being equal. The two deltatheta values of C-H bonds flanking the cis-double bond are smaller than that obtained for adjacent CH2 groups by a factor of 1.5-2. Defining these properties is a necessary step to gaining a more complete understanding of polyunsaturated lipid hydrocarbon chains significance. The mean molecule magnitudes of ¿S(CH)¿ decrease when unsaturation increases. The cis-double bond parameters S(CC) are found to be higher than those of adjacent single C-C bonds: the parameter S(CC) odd-even effect in the polyunsaturated molecules of such structure changes the "sign" between double bonds. The order parameter profiles -S(CH) of cis-18:1 and cis-18:2 obtained from the simulations (at the portion which corresponds to the double bonds location) are in qualitative agreement with experimental data on bilayers in the liquid-crystal phase. This has made possible the quantitative prognosis of the ordering properties of experimentally uninvestigated unsaturated lipids.

Molecular dynamics investigation of bond ordering of unsaturated lipids in monolayers.

Molecular dynamics simulations of three model lipid monolayers of 2,3-diacyl-D-glycerolipids, that contained stearoyl (18:0) in the position 3 and oleoyl (18:ω9cis), linoleoyl (18:2ω6cis), or linolenoyl (18:3ω3cis) in the position 2, have been carried out. The simulation systems consisted of 24 lipid molecules arranged in a rectangular simulation cell, with periodic boundary conditions in the surface plane. 1 nanosecond simulations were performed at T = 295 K. C-C and C-H bond order parameter profiles and the bond orientation distributions about the monolayer normal have been calculated. The relation of the distributions to the order parameters was analyzed in terms of maxima and widths of the distributions. The cis double bond order parameter is found to be higher than those of adjacent single C-C bonds. The widths of the two distributions of C-H bonds of the cis double bond segment in di- and triunsaturated molecules are much smaller than that obtained for methylene group located between the double bonds. The bond orientation distribution function widths depend on both the segment location in the chain and the segment chemical structure.

[Intramolecular bond ordering of cis-octadecadienoic chains of natural lipids. Monte-Carlo simulation]. / Vnutrimolekuliarnaia uporiadochennost' sviazei tsis-oktadekadienovykh tsepei prirodnykh lipidov. Modelirovanie metodom Monte-Karlo.

The Monte Carlo method is applied in the calculation of C-C and C-H bond orientation distributions rho(theta) with respect to the maximum molecule span axis (theta is the angle between the bond and the axis) and bond order parameters SCC and SCH of isolated unperturbed hydrocarbon chains of cis -C18;2 at T = 298 K. The molecule-fixed coordinate system is used. The relation of the bond orientation distributions rho(theta) to the order parameters S are analysed in terms of angles theta max (a "geometric" factor, rho(theta max) = max) and widths delta theta of the distributions (factor of "fluctuations"). The results indicate that the fluctuation factor depends on both the segment chemical structure and location in the chain. The two delta theta values of C-H-bonds flanking the double bond are smaller than that obtained for adjacent CH2-groups by a factor of 1.5-2. The C = C double bond parameters SCC are found to be higher than those of adjacent single C-C bonds. The order parameter profiles -SCH obtained from the simulations (at the portion which corresponds to the double bonds location) are in qualitative, agreement with experimental data on the bilayer in the liquid-crystal phase.

[Modeling the dynamics of polyunsaturated lipids in biological membranes]. / Modelirovanie dinamiki polinenasyshchennykh lipidov biologicheskikh membran.

Molecular dynamics simulations were performed for the docosahexaene C22H34 and docosan C22H46 chains, which are typical components of phospholipids in biological membranes. The calculations were carried on at two temperatures of 276 K and 320 K. The time of each computation covered 600 ps. The torsion angles variations phi i(t), i = 1, 2, ..., 21 has been analysed. It has been demonstrated that in docosan phi i(t) are oscillating with the amplitudes of 10-15 degrees, which are slightly increasing with the temperature. The average torsion angle positions correspond to the rotation-isomeric model. In docosahexaene chain the amplitudes of the torsion angles oscillations around a simple bond, connected to a double one, are about twice greater and their frequencies are about 3.5 times less then the docosan have. It has been noted that these angles also possess states, living up to 5 ps, which do not correspond to the regions of the minimum potential energy of molecular fragments. Average frequency of conformational transitions in docosahexaene chain is about six times greater than in the docosan one.

On the conformational, physical properties and functions of polyunsaturated acyl chains.

The conformational properties of the acyls of biological membranes--hydrocarbon chains with isolated cis double bonds--were studied by computer simulation. The Monte Carlo method was used, with continuous variation of bond rotation angles within the (0, 360 degree) range considered. It has been shown, that if all double bonds of molecules are separated only by one methylene group, and their number in the chain is maximum, the molecule is characterized by the highest equilibrium flexibility (at temperatures only encountered by biological systems) as compared to any similar molecules. It is such a structure which is inherent to docosahexaenoic acid. The above molecule coefficient that characterizes the temperature sensitivity of the molecule sizes is 10-times lower than that of a saturated chain. The polyunsaturated chain segment with high probability assumes the extended (in perfect crystal structures the 'angle iron-shaped') conformation when all the molecules are efficiently packed below the phase-transition temperatures. The annular lipid layer of embedded enzymes is assumed to be enriched with polyunsaturated fatty acid acyls. The above physical properties of polyunsaturated chains are bound to favour the maintenance of the proper conformational mobility of biomembrane enzymes, to relax the negative influence of environmental temperature changes on their activity. When freezing biological membranes they are bound to provide the molecule packing which is free of high tensions.