Conformation and packing properties of membrane lipids: the crystal structure of sodium dimyristoylphosphatidylglycerol

The conformation and molecular packing of sodium 1,2-dimyristoyl-sn-glycero-phospho-rac-glycerol (DMPG) have been determined by single crystal analysis (R = 0.098). The lipid crystallizes in the monoclinic spacegroup P2(1) with the unit cell dimensions a = 10.4, b = 8.5, c = 45.5 A and beta = 95.2 degrees. There are two independent molecules (A and B) in the asymmetric unit which with respect to configuration and conformation of their glycerol headgroup are mirror images. The molecules pack tail to tail in a bilayer structure. The phosphoglycerol headgroups have a layer-parallel orientation giving the molecules an L-shape. At the bilayer surface the (-) phosphoglycerol groups are arranged in rows which are separated by rows of (+) sodium ions. Laterally the polar groups interact by an extensive network of hydrogen, ionic and coordination bonds. The packing cross-section per molecule is 44.0 A2. The hydrocarbon chains are tilted (29 degrees) and have opposite inclination in the two bilayer halves. In the chain matrix the chain planes are arranged according to a so far unknown hybride packing mode which combines the features of T parallel and O perpendicular subcells. The two fatty acid substituted glycerol oxygens have mutually a - synclinal rather than the more common + synclinal conformation. The conformation of the diacylglycerol part of molecule A and B is distinguished by an axial displacement of the two hydrocarbon chains by four methylene units. This results in a reorientation of the glycerol back bone and a change in the conformation and stacking of the hydrocarbon chains. In molecule A the beta-chain is straight and the gamma-chain is bent while in molecule B the chain conformation is reversed.     

The influence of lysolipids on the spontaneous curvature and bending elasticity of phospholipid membranes.

The effects of lysolipids on phospholipid layer curvature and bending elasticity were examined using x-ray diffraction and the osmotic stress method. Lysolipids with two different head groups, phosphatidylcholine (PC) and phosphatidylethanolamine (PE), and differing hydrocarbon chains were mixed with the hexagonal-forming lipid, dioleoylphosphatidylethanolamine (DOPE). With up to 30 mole% lysolipid in DOPE, the mixture maintains the inverted hexagonal (H(II)) phase in excess water, where increasing levels of lysolipid result in a systematic increase in the H(II) lattice dimension. Analysis of the structural changes imposed by lysolipids show that, opposite to DOPE itself, which has an spontaneous radius of curvature (R(0)) of -30 A, PC lysolipids add high positive curvature, with R(0) = +38 to +60 A, depending on chain length. LysoPEs, in contrast, add very small curvatures. When both polar group and hydrocarbon chains of the added lysolipid mismatch those of DOPE, the structural effects are qualitatively different from otherwise. Such mismatched lysolipids "reshape" the effective combination molecule into a longer and more cylindrical configuration compared to those lysolipids with either matching polar group or hydrocarbon chain.     

A self-consistent chain model for the phase transitions in lipid bilayer membranes

We presented a mechanical model of a lipid bilayer membrane. The internal conformations of a polar head group and double hydrocarbon chains in a lipid molecule were described on the basis of the isomeric bond-rotation scheme. The thermodynamic properties of the lipid membranes were represented by a density matrix that described the rotational isomeric states of the head groups and chains. The parameters that determined the density matrix were obtained in the presence of the intermolecular interactions, which depend on the conformation of the molecules. The interchain interaction was given by the Kihara potential, which depends on the shape of the chains. The Coulomb interaction between the polar head groups and the lateral pressure were considered. The calculation was made for the three lipid molecules corresponding to DMPC, DPPC, and DSPC. The model agreed well with the following experimental results: the temperature, the latent heat of the gel-to-liquid crystalline phase transition, the temperature dependencies of (a) the intermolecular distance, (b) the number of gauche bonds in a hydrocarbon chain, (c) the order parameter for the bond orientation, (d) the volume of the membrane, (e) the thermal expansion coefficients, and (f) the birefringence.     

Structural dimensions and their changes in a reentrant hexagonal-lamellar transition of phospholipids.

A hexagonal-lamellar-hexagonal (HII-L-HII) reentrant phase transition sequence on dehydration of dioleoylphosphatidylethanolamine occurs below 22 degrees C. This provides an unusual opportunity to measure how several structural dimensions change during this transition. Using x-ray diffraction, we have measured these dimensions with a hope of gaining some clue about the accompanying internal stresses. The principal dimensions described are molecular areas and molecular lengths projected onto the hexagonal lattice. In contrast with large changes in average area at the polar and hydrocarbon ends of the molecule, a position near the polar group/hydrocarbon interface is one of constant molecular area. It remains constant both as the monolayers curl from changing water content and in the transition from one structure to the other. In the L-to-HII transition, the most obvious change in molecular length is a 25% decrease in the distance between aqueous cylinders, the interaxial direction. There is little change in the interstitial direction, the direction toward the interstice equidistant from three aqueous cylinders. As the hexagonal phase is dehydrated, a number of internal changes in molecular lengths are described. Increases in the interaxial direction are much larger than in the interstitial. Simultaneously however, hydrocarbon chain lengths decrease, and polar group lengths increase. It is likely that molecules move axially and the cylinders become longer with dehydration. These dimensions and their changes might be used in the search for a better understanding of the energetics of molecular packing, of the interpretation of spectroscopic measurements of these phases, and of the mechanics of lipid layers.     

Solvent accessibilities in glycyl, alanyl and seryl dipeptides.

Theoretical studies on glycyl-alanyl and seryl dipeptides were performed to determine the probable backbone and side-group conformations that are preferred for solvent interaction. By following the method of Lee & Richards [(1971) J. Mol. Biol. 55, 379-400], a solute molecule is represented by a set of interlocking spheres of appropriate van der Waals radii assigned to each atom, and a solvent (water) molecule is rolled along the envelope of the van der Waals surface, and the surface accessible to the solvent molecule, and hence the solvent accessibility for a particular conformation of the solute molecule, is computed. From the calculated solvent accessibilities for various conformations, solvation maps for dipeptides were constructed. These solvation maps suggest that the backbone polar atoms could interact with solvent molecules selectively, depending on the backbone conformation. A conformation in the right-handed bridge (zetaR) region is favoured for both solvent interaction and intrachain hydrogen-bonding. Also the backbone side-chain hydrogen-bonding within the same dipeptide fragment in proteins is less favoured than hydrogen-bonding between side chain and water and between side chain and atoms of other residues. Solvent accessibilities suggest that very short distorted alphaR-helical and extended-structural parts may be stabilized via solvent interaction, and this could easily be possible at the surface of the protein molecules, in agreement with protein-crystal data.     

On the use of deuterium nuclear magnetic resonance as a probe of chain packing in lipid bilayers

The packing of hydrocarbon chains in the bilayers of lamellar (L alpha) phases of soap/water and phospholipid/water mixtures has been studied by deuterium NMR spectroscopy and X-ray diffraction. A universal correlation is shown to exist between the average C-D bond order parameter SCD of hydrocarbon chains and the average area per chain ach, irrespective of the chemical structure of the surfactant (hydrophilic group, number of chains per molecule, and chain length), composition, and temperature. The practical utility of the correlation is illustrated by its application to the characterization of the distribution of various hydrophobic and amphiphilic solutes in bilayers. The distribution of hydrocarbons within a bilayer is shown to depend upon their molecular structure in a manner which highlights the nature of the molecular interactions involved. For example, benzene is shown to be fairly uniformly distributed across the bilayer with an increasing tendency to distribute into the center at high concentrations. In contrast, the more complex hydrocarbon tetradecane preferentially distributes into the center of the bilayer at low concentrations, while at higher concentrations it intercalates between the surfactant chains. Alcohols such as benzyl alcohol, octanol, and decanol all interact similarly with the bilayer in so far as they are pinned to the polar/apolar interface, presumably by involvement of the hydroxyl group in a hydrogen bond. But the response of the surfactant chains to the void volume created in the center of the bilayer is dependent upon the distance of penetration of the alcohol into the bilayer. For benzyl alcohol, the shortest molecule, this void volume is taken up by the disordering of the chains, while for decanol, the longest molecule, it is absorbed by interdigitation of the chains of apposing monolayers. For octanol, the chain interdigitation mechanism is dominant at low concentrations, but there is a transition to chain disordering at high concentrations. Finally, it is shown that the correlation provides a useful test for statistical mechanical models of chain ordering in lipid bilayers.     

Molecular parameters and conformation of globoside and asialo-GM1

Comparative studies of the individual properties and intermolecular organization of asialo-GM1 (Gg4Cer) and globoside (Gb4Cer) were made employing lipid monolayers and high-sensitivity differential scanning calorimetry. The surface pressure-area isotherm of Gb4Cer is more expanded than that of Gg4Cer. This results in greater molecular areas and compressibilities, and lower intermolecular interaction energies, for Gb4Cer compared to Gg4Cer at all surface pressures. This looser intermolecular packing may be responsible for a lower transition temperature (40.5 degrees C) and enthalpy of transition (delta Hcal) (2.0 kcal mol-1) found for the phase transition of Gb4Cer compared to Gg4Cer (54.0 degrees C and 4.2 kcal mol-1). The surface potential per molecule and resultant molecular dipole moment vector values are greater for Gb4Cer than for Gg4Cer at comparable values of surface pressure and molecular area. All these results reflect the existence of a rigid L-shape in the oligosaccharide chain of Gb4Cer that prevents a close intermolecular packing compared to the straight orientation of the polar head group of Gg4Cer. Significant movements of the oligosaccharide chain may occur depending on the lateral surface pressure. At low surface pressures the orientation of the oligosaccharide chain of Gg4Cer may be displaced an angle of up to about 40 degrees compared to the perpendicular position adopted at high surface pressures. In agreement with an enhanced liquid character of the interface, the oligosaccharide chain of Gb4Cer exhibits a greater freedom of movement and the displacement from the position perpendicular to the interface can reach to about 65 degrees.     

Water-protein interactions from high-resolution protein crystallography

To understand the role of water in life at molecular and atomic levels, structures and interactions at the protein-water interface have been investigated by cryogenic X-ray crystallography. The method enabled a much clearer visualization of definite hydration sites on the protein surface than at ambient temperature. Using the structural models of proteins, including several hydration water molecules, the characteristics in hydration structures were systematically analysed for the amount, the interaction geometries between water molecules and proteins, and the local and global distribution of water molecules on the surface of proteins. The tetrahedral hydrogen-bond geometry of water molecules in bulk solvent was retained at the interface and enabled the extension of a three-dimensional chain connection of a hydrogen-bond network among hydration water molecules and polar protein atoms over the entire surface of proteins. Networks of hydrogen bonds were quite flexible to accommodate and/or to regulate the conformational changes of proteins such as domain motions. The present experimental results may have profound implications in the understanding of the physico-chemical principles governing the dynamics of proteins in an aqueous environment and a discussion of why water is essential to life at a molecular level.     

Identifying the Interaction of Vancomycin With Novel pH-Responsive Lipids as Antibacterial Biomaterials Via Accelerated Molecular Dynamics and Binding Free Energy Calculations

Nano-drug delivery systems have proven to be an efficient formulation tool to overcome the challenges with current antibiotics therapy and resistance. A series of pH-responsive lipid molecules were designed and synthesized for future liposomal formulation as a nano-drug delivery system for vancomycin at the infection site. The structures of these lipids differ from each other in respect of hydrocarbon tails: Lipid1, 2, 3 and 4 have stearic, oleic, linoleic, and linolenic acid hydrocarbon chains, respectively. The impact of variation in the hydrocarbon chain in the lipid structure on drug encapsulation and release profile, as well as mode of drug interaction, was investigated using molecular modeling analyses. A wide range of computational tools, including accelerated molecular dynamics, normal molecular dynamics, binding free energy calculations and principle component analysis, were applied to provide comprehensive insight into the interaction landscape between vancomycin and the designed lipid molecules. Interestingly, both MM-GBSA and MM-PBSA binding affinity calculations using normal molecular dynamics and accelerated molecular dynamics trajectories showed a very consistent trend, where the order of binding affinity towards vancomycin was lipid4?>?lipid1?>?lipid2?>?lipid3. From both normal molecular dynamics and accelerated molecular dynamics, the interaction of lipid3 with vancomycin is demonstrated to be the weakest (?G_binding?=??2.17 and ?11.57, for normal molecular dynamics and accelerated molecular dynamics, respectively) when compared to other complexes. We believe that the degree of unsaturation of the hydrocarbon chain in the lipid molecules may impact on the overall conformational behavior, interaction mode and encapsulation (wrapping) of the lipid molecules around the vancomycin molecule. This thorough computational analysis prior to the experimental investigation is a valuable approach to guide for predicting the encapsulation ability, drug release and further development of novel liposome-based pH-responsive nano-drug delivery system with refined structural and chemical features of potential lipid molecule for formulation development.     

The structure of a model membrane in relation to the viscoelastic properties of the red cell membrane

The molecular arrangement within a lamellar structure composed of human erythrocyte lipids is determined. The 45 A thick lipid layer, in water, is filled in the interior with a liquid-like configuration of the hydrocarbon chains of phospholipid molecules and is covered on both sides by their hydrophilic polar groups. Cholesterol is located so that part of its steroid nucleus is between the polar groups of the phospholipid molecules while the rest of the molecule extends into the inner hydrocarbon layer. This lipid leaflet would be expected to have the mechanical properties of a purely liquid surface, as other authors have shown for the "black" lipid membranes. Data are presented which demonstrate that the intact erythrocyte membrane is a tough viscoelastic substance with a Young''s modulus of 10⁶–10⁸ dynes/cm² and a viscosity of 10⁷–10¹⁰ poises. The parameters and the kinetics of membrane breakdown are incompatible with the model system of pure lipid. Caution must be exercised in applying various data on the model systems to intact membranes.     

Theoretical study of 1-(4-hexylcyclohexyl)-4-isothiocyanatobenzene: molecular properties and spectral characteristics

The mesogenic species 4-(4-hexylcyclohexyl) isothiocyanatobenzene (6CHBT) was studied with density functional theory and molecular mechanics in order to investigate the molecular properties, interactions between dimers and to interpret the IR spectrum. Two types of calculations were performed for model systems containing single and double molecules of 6CHBT. Calculations (involving conformation analysis) for isolated species indicated that the trans isomer, in the equatorial–equatorial conformation, is the most energetically stable. The 6CHBT molecule is polar, with a rather high (4.43 D) dipole moment with negatively charged isothiocyanato (NCS) ligand. The dimer–dimer interaction energies show that the head-to-head configuration (where van der Waals attraction forces play the major role) is the most energetically stable. Vibrational analysis provided detailed assignment of the experimental infra-red (IR) spectrum. Figure Most favorite 6CHBT head to head interaction - ESP mapped to electron density surface Dedication  This paper is dedicated to the memory of Dr. Wacław Witko, who introduced us to research on mesogenic systems.     

Molecular dynamics simulation of GM1 in phospholipid bilayer

We report molecular dynamics simulation of fully hydrated lipid bilayer of dimyristoyl phosphatidyl choline (DMPC) at room temperature with ganglioside GM1 attached to it in the upper layer under periodic boundary conditions. The simulation results indicate that the presence of a single GM1 molecule has local effects on the bilayer. Three sugar residues (GalNAc-Gal-Glc) of the pentasaccharide head group of GM1 remain on the lipid surface where as the NeuNAc residue extends out in the aqueous layer. The radial distribution functions suggest ordering of water molecules near the glycerol and carboxyl group of the sialic acid in the upper layer. One of the ceramide chains of GM1, the sphingosine chain, folds up and is stacked under the sugar residues lying on the surface. The other ceramide chain is inserted into the lipid bilayer. The arrangement of the polar head group as well as the acyl chains of the lipids which are immediate neighbours of the GM1 are modified compared to the non-neighbour ones and others at the lower layer. The time average conformation of GM1-pentasaccharide is stabilized by a number of inter residue hydrogen bonds that were observed experimentally. The trajectory average conformation of GM1-pentasaccharide was docked on to the cholera toxin molecule and the minimized complex reveals alternative binding modes between the toxin and the GM1-pentasaccharide moiety. The results of these simulation studies might help to understand the structure and nature of the effects of GM1 on the membrane at atomic resolution.     

Iron binding to alpha-tocopherol-containing phospholipid liposomes

Tocopherols (vitamin E) located in the hydrophobic domains of biological membranes act as chain breaking antioxidants preventing the propagation of free radical reactions of lipid peroxidation. The naturally occurring form, d-alpha tocopherol is an exquisite molecule in that it is intercalated in the membrane in such a way that the hydrophobic tail anchors the molecule positioning the chromanol ring containing the hydroxyl group, which is the essence of its antioxidant function, at the polar hydrocarbon interface of phospholipid membranes. The interaction of this group with water soluble substances is not very well understood. In the present study, an investigation was made of the interaction of ascorbate and ferrous ions (Fe+2) initiators of lipid peroxidation with alpha tocopherol. The results show that tocopherol increases membrane associated iron. The formation of a tocopherol iron complex in the presence of phospholipid liposomes and ascorbate in its reduced form is indicated. These results suggest a new way in which tocopherols act to inhibit lipid peroxidation.     

Surface areas and packing constraints in POPC C (12)EO (n) membranes. A time-resolved fluorescence study

The surface area occupied by nonionic detergents of the type C(12)EO(n) (n = 1-8) in POPC C (12)EO (n) mixed membranes was studied by means of time-resolved resonance energy transfer (RET) between the fluorescent probe molecules NBD-PE and rhodamine-PE. The area data were interpreted within the frame of Israelachvili's concept of packing constraints yielding the critical packing parameter, f, as a measure of the asymmetry of the molecular shape of the membrane constituents. The asymmetry of the molecular shape of the detergent increases with the ethylene oxide chain length and correlates with the potency of the detergent to solubilize the bilayers and the reduction of the DPH order parameter. For n = 1-3, the membrane surface was found to expand by 0.25-0.30 nm(2) per incorporated C(12)EO(n) molecule. This value corresponds to the cross section of one hydrocarbon chain in liquid-crystalline phases. On increasing n from n = 4 to n = 8 the net area per detergent molecule increases from 0.43 nm(2) to 1.16 nm(2). These surface requirements are consistent with a disordered, coiled conformation of the EO-chains hydrated with up to two water molecules per ethylene oxide unit. For n > 5 the limiting mole fraction of the bilayer saturation was deduced from the f-data in the two-component bilayer. DPH and NBD-PE fluorescence lifetime data are discussed to give an indication of the accessibility of the probe environment to water molecules.     

The noneffect of a large linear hydrocarbon, squalene, on the phosphatidylcholine packing structure.

The interaction of squalene with liposomes and monolayers of dipalmitoyl phosphatidylcholine (DPL) has been studied by differential scanning calorimetry, Raman spectroscopy, and surface potential measurements. Mole ratios of squalene to DPL up to 9 to 1 were studied. In contrast to small, nonpolar molecules, which profoundly influence the structure of lipid bilayers as detected by changes in both their thermodynamic phase transition parameters and membrane fluidity, this large, nonpolar, linear hydrocarbon is devoid of such influences. It is clear from our data that a large nonpolar molecule such as squalene, having no polar group that might anchor it to the aqueous interface, cannot intercalate between the acyl chains either below or above the phase transition of DPL. This behavior is not compatible with models that treat the bilayer interior as a bulk hydrocarbon, and suggests that great caution should be exercised in extrapolating partition coefficients based on bulk hydrocarbon measurements to lipid bilayers.     

Interaction of small molecules with phospholipid bilayer membranes: A spin label study

Multilamellar spin labelled liposomes were prepared from dipalmitoyl or dimyristoyl phosphatidylcholine, dicetyl phosphate, and the spin probe 12-doxyl stearate methyl ester. The effects of a series of benzene and adamantane derivatives, on fatty acyl chain motion was measured through changes in the electron spin resonance spectra of these liposomes. All the compounds tested, increased lipid chain motion to a variable degree. In general, molecules possessing a polar group were more potent than those lacking such a group and lipophilicity per se correlated poorly with the relative order of these compounds. Within the adamantane series separating the polar group from the cage structure by the insertion of methylene groups further enhanced the capacity of the molecule to increase hydrocarbon chain mobility. These observations are consistent with the hypothesis that the location of the additive within the bilayer is the main determinant of its effectiveness in increasing fatty acyl chain motion.     

DFT study of water adsorption on lignite molecule surface

High moisture content is a main characteristic of low-rank coal, such as lignite. Numerous oxygen containing functional groups in lignite make it represent some special properties, and these functional groups affect the adsorption mechanisms of water molecules on lignite surface. This study reports some typical water?·?·?·?lignite conformations, along with a detailed analysis of the geometry, electrostatic potential distribution, reduced density gradient of interaction, and interaction energy decomposition. The results show that water molecules tend to aggregate around functional groups, and hydrogen bonds play a dominant role in the interaction. The adsorption energy of water cluster on lignite surface is larger than that of isolated water molecule, a good linear relationship between the interaction distance and adsorption energy of layers has been found. Since water is a polar molecule, the local minima and maxima of electrostatic potential in conformations increase along with more water adsorbing on lignite surface. Reduced density gradient analysis shows that H-bonds, van der Waals interaction, and a little steric make up the interaction between water cluster and lignite molecule. In these studied conformations which mainly are H-bond complexes, electrostatic and exchange repulsion play a dominant role, whereas polarization and dispersion make relatively small contribution to the interaction. Attractive and repulsive interaction both affect the stability of water?·?·?·?lignite conformations.     

Electrostatic potential and Born energy of charged molecules interacting with phospholipid membranes: calculation via 3-D numerical solution of the full Poisson equation.

Understanding the physicochemical basis of the interaction of molecules with lipid bilayers is fundamental to membrane biology. In this study, a new, three-dimensional numerical solution of the full Poisson equation including local dielectric variation is developed using finite difference techniques in order to model electrostatic interactions of charged molecules with a non-uniform dielectric. This solution is used to describe the electric field and electrostatic potential profile of a charged molecule interacting with a phospholipid bilayer in a manner consistent with the known composition and structure of the membrane. Furthermore, the Born interaction energy is then calculated by appropriate integration of the electric field over whole space. Numerical computations indicate that the electrostatic potential profile surrounding a charge molecule and its resultant Born interaction energy are a function of molecular position within the membrane and change most significantly within the polar region of the bilayer. The maximum interaction energy is observed when the charge is placed at the center of the hydrophobic core of the membrane and is strongly dependent on the size of the charge and on the thickness of the hydrocarbon core of the bilayer. The numerical results of this continuum model are compared with various analytical approximations for the Born energy including models established for discontinuous slab dielectrics. The calculated energies agree with the well-known Born analytical expression only when the charge is located near the center of a hydrocarbon core of greater than 60 A in thickness. The Born-image model shows excellent agreement with the numerical results only when modified to include an appropriate effective thickness of the low dielectric region. In addition, a newly derived approximation which considers the local mean dielectric provides a simple and continuous solution that also agrees well with the numerical results.     

Molecular arrangements of sphingolipids. The monolayer behaviour of ceramides

A series of synthetic ceramides have been studied at the air-water interface by recording the surface pressure-area isotherms at continuous compression.

Ceramides that contain a 4,5-trans-double bond in the long chain base were found to condense into a close-packed arrangement with vertical chains already at a very low surface pressure. The corresponding saturated compounds adopt a similar close packed arrangement only at high surface pressure. At 30 dynes/cm, a lateral pressure representative of biological membranes, the area per molecule and compressibility was further found to depend on the number and configuration of the hydroxyl groups. The presence of a 2-D-hydroxyl group in the fatty acud generally promotes the condensation. A similar effect is observed if the long chain base contains a 4-D-hydroxyl group. Cis-double bonds or methyl branches in the fatty acid chain, which increase the space requirement, limit the lateral interaction of the polar group. However the 15-cis-double bond of nervonic acid can be accommodated without any distortion of the close-packing arrangement.     

生物分子水溶液的蒙特卡罗模拟——Ⅱ.缬氨酸溶液

本文对由115个水分子包围一个中性缬氨酸分子所组成的分子集团做了蒙特卡罗模拟.模拟的温度是298K.对缬氨酸羧基区、氨基区和异丙基区分别提取了平均水—水和水—缬氨酸分子的相互作用能的径向分布函数,水分子的氧原子和氢原子的径向分布函数以及水分子偶极矩的取向关联函数.此外,我们还求出了所模拟溶液的构型比热和缬氨酸分子分区及全体的第一个水化层的平均水分子数.