Alexander L. Rabinovich

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.

Force Field Development for Lipid Membrane Simulations

With the rapid development of computer power and wide availability of modelling software computer simulations of realistic models of lipid membranes, including their interactions with various molecular species, polypeptides and membrane proteins have become feasible for many research groups. The crucial issue of the reliability of such simulations is the quality of the force field, and many efforts, especially in the latest several years, have been devoted to parametrization and optimization of the force fields for biomembrane modelling. In this review, we give account of the recent development in this area, covering different classes of force fields, principles of the force field parametrization, comparison of the force fields, and their experimental validation. This article is part of a Special Issue entitled: Biosimulations edited by Ilpo Vattulainen and Tomasz Róg.

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.

Computer simulation of lipid membranes: Methodology and achievements

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 7 years, and covering only several selected subjects: methodological (development of the force fields for lipid bilayer simulations, use of coarse-grained models) and scientific (studies of the role of lipid unsaturation, and the effect of cholesterol and other inclusions on properties of the bilayer).

The flexibility of natural hydrocarbon chains with non-methylene-interrupted double bonds

Abstract The question of a possible functional role of acyls with non-methylene-interrupted double bonds in biomembranes is discussed. Comparative analysis was made of the flexibility of hydrocarbon chains with 18 carbon atoms containing 1–5 isolated cis double bonds, between which 1 10 CH2 groups are located. The results are obtained by computer simulation of the conformational behaviour of molecules at 298 K. The inter-arrangement of double bonds and their localization in a chain is of a great importance for definition of its flexibility: in the case of non-methylene-interrupted double bonds a growth of their number in a chain does not always result in increased flexibility of the molecule.

Properties of unsaturated phospholipid bilayers: Effect of cholesterol

Properties of hydrated unsaturated phosphatidylcholine (PC) lipid bilayers containing 40 mol % cholesterol and of pure PC bilayers have been studied. Various methods were applied, including molecular dynamics simulations, self-consistent field calculations, and the pulsed field gradient nuclear magnetic resonance technique. Lipid bilayers were composed of 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. Lateral self-diffusion coefficients of the lipids in all these bilayers, mass density distributions of atoms and atom groups with respect to the bilayer normal, the C-H and C-C bond order parameter profiles of each phospholipid hydrocarbon chain with respect to the bilayer normal were calculated. It was shown that the lateral self-diffusion coefficient of PC molecules of the lipid bilayer containing 40 mol % cholesterol is smaller than that for a corresponding pure PC bilayer; the diffusion coefficients increase with increasing the degree of unsaturation of one of the PC chains in bilayers of both types (i.e., in pure bilayers or in bilayers with cholesterol). The presence of cholesterol in a bilayer promoted the extension of saturated and polyunsaturated lipid chains. The condensing effect of cholesterol on the order parameters was more pronounced for the double C=C bonds of polyunsaturated chains than for single C-C bonds of saturated chains.

Comparative investigation of lipid membrane systems

Molecular dynamics (MC) simulations of bilayers consisted of (1) phosphatidylcholines (PC) and (2) diacylglycerolipids (DG), and lattice-based molecular-level self-consistent field (SCF) calculations of the model lipid bilayers were carried out. Lipid molecules with acyl chains of 18:0/18:0, 18:0/18:1(omega) 9cis, 18:0/18:2(omega) 6cis, 18:0/18:3(omega) 3cis, 18:0/20:4(omega) 6cis, 18:0/22:6(omega) 3cis were investigated. The C-H and C-C bond order parameter (-SCH, SCC) profiles of the hydrocarbon tails, the bond orientation distribution functions, the root-mean-square values of the positional fluctuations of the lipid chain carbons were calculated. The theoretical results are compared with the available experimental data. The main qualitatively characteristic features of the properties of bilayer with lipid chains of a given chemical structure show up in both the MD and in the SCF results. The key physical properties of lipid bilayers that are composed of unsaturated lipids are discussed from a theoretical perspective.

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.

Bond orientation properties in lipid molecules of membranes: molecular dynamics simulations

Atomistic molecular dynamics simulations have been carried out for 16 different fully hydrated phosphatidylcholine lipid bilayers, having 16 or 18 carbon atoms in fully saturated sn − 1 chain and from 18 to 22 carbon atoms in sn − 2 chain with different degree of unsaturation, with the purpose to investigate the effect of unsaturation on physical properties of lipid bilayers. Special attention has been paid to profiles of C-C and C-H bond order parameters of lipid molecules and the orientational fluctuations of these bond vectors. It was shown that the study of anisotropy degree of bond orientations probability distributions allows distinguishing extended regions with different types of angular fluctuations of bonds in a membrane formed by lipid molecules with unsaturated chains.

Molecular dynamics investigation of polar diacylglycerolipid monolayers: bond ordering properties

Molecular dynamics simulations of six monolayers composed of the molecules 2,3-diacyl-D-glycerolipids that contained stearoyl in the position 3 and stearoyl, oleoyl, linoleoyl, linolenoyl, arachidonoyl or docosahexaenoyl in the position 2 have been carried out; 1.5 nanosecond simulations were performed at T equals 303 K for the monolayers of unsaturated molecules and at T equals 326 K for saturated one. The average areas per lipid molecule over the simulations were 65.6 angstroms2 in 18:0/18:0-monolayer, 66.2 angstroms2 in 18:0/18:1(omega) 9cis-monolayer, 66.1 angstroms2 in 18:0/18:2(omega) 6cis-, 67.4 angstroms2 in 18:0/18:3(omega) 3cis-, 70.6 angstroms2 in 18:0/20:4(omega) 6cis- and 71.4 angstroms2 in 18:0/22:6(omega) 3cis-monolayer. The C-H bond orientation distributions and C-H bond order parameters profiles about the monolayer normals have been calculated. The bond orientation distribution function widths turned out to be depended on both the segment location in the chain and the segment chemical structure. The computer simulation data indicated the widths of the distributions of CH2-groups located between the double bonds of polyunsaturated chains to be much greater than that of C-H bonds of double bond carbons (broadening effect).