CiteULike: softsimu's library [5654 articles]

Inhibition of human liver catechol-O-methyltransferase by tea catechins and their metabolites: Structure-activity relationship and molecular-modeling studies

Dapeng Chen — 2008-06-30T19:54:22-00:00

Biochemical Pharmacology, Vol. 69, No. 10. (15 May 2005), pp. 1523-1531.

(-)-Epigallocatechin-3-gallate (EGCG) is the major polyphenol present in green tea. We previously demonstrated that EGCG was both a substrate and potent inhibitor of human liver cytosolic catechol-O-methyltransferease (COMT). We now report the structure-activity relationship for the inhibition of COMT-catalyzed O-methylation of catecholestrogens in human liver cytosol by tea catechins and some of their metabolites. The most potent inhibitors were catechins with a galloyl-type D-ring, including EGCG (IC50 = 0.07 [mu]M), 4”-O-methyl-EGCG (IC50 = 0.10 [mu]M), 4',4”-di-O-methyl-EGCG (4',4”-DiMeEGCG) (IC50 = 0.15 [mu]M), and (-)-epicatechin-3-gallate (ECG) (IC50 = 0.20 [mu]M). Catechins without the D-ring showed two to three orders of magnitude less inhibitory potency. Enzyme kinetic analyses revealed that EGCG behaved as a mixed inhibitor, whereas 4',4”-di-O-methyl-EGCG exhibited competitive kinetics for the S-adenosylmethionine (SAM), and noncompetitive kinetics for the catechol binding site. These compounds may represent a new type of COMT inhibitor. In silico molecular-modeling studies using a homology model of human COMT were conducted to aid in the understanding the catalytic and inhibitory mechanisms. Either D-ring or B-ring of EGCG could be accommodated to the substrate binding pocket of human COMT. However, the close proximity (2.6 Å) of 4”-OH to the critical residue Lys144, the higher acidity of the hydroxyl groups of the D-ring, and the hydrophobic interactions between the D-ring and residues in the binding pocket greatly facilitated the interaction of the D-ring with the enzyme, and resulted in increased inhibitory potency. These results provide mechanistic insight into the inhibition of COMT by commonly consumed tea catechins.

Bead--bead interaction parameters in dissipative particle dynamics: Relation to bead-size, solubility parameter, and surface tension

Amitesh Maiti — 2008-06-30T19:34:19-00:00

The Journal of Chemical Physics, Vol. 120, No. 3. (2004), pp. 1594-1601.

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Lipid Rafts: Feeling is Believing

Henderson — 2008-06-27T21:13:23-00:00

News Physiol. Sci., Vol. 19 (2004), pp. 39-43.

The equilibrium of phosphatidylcholine-cholesterol in monolayers at the air/water interface

Izabela Brzozowska — 2008-06-27T21:10:02-00:00

Colloids and Surfaces B: Biointerfaces, Vol. 23, No. 1. (January 2002), pp. 51-58.

Monolayers of either cholesterol (Ch) or phosphatidylcholine (L) or their mixtures were investigated at the air/water interface. The surface tension values of pure and mixed monolayers were used to calculate the [pi]-A isotherms. The theory of equilibrium between components of monolayers at the air/water interface has been developed in order to obtain the stability constant of the Ch-L complex. We considered the equilibrium between L, Ch and the L-Ch complex on the basis of derived equations. We established that egg lecithin and cholesterol formed a 1:1 complex, with stability constant equal to K=2.56×106.

Gating Mechanisms of Mechanosensitive Channels of Large Conductance, II: Systematic Study of Conformational Transitions

Yuye Tang — 2008-06-26T20:58:59-00:00

Biophys. J., Vol. 95, No. 2. (15 July 2008), pp. 581-596.

Part II of this study is based on the continuum mechanics-based molecular dynamics-decorated finite element method (MDeFEM) framework established in Part I. In Part II, the gating pathways of Escherichia coli-MscL channels under various basic deformation modes are simulated. Upon equibiaxial tension (which is verified to be the most effective mode for gating), the MDeFEM results agree well with both experiments and all-atom simulations in literature, as well as the analytical continuum models and elastic network models developed in Part I. Different levels of model sophistication and effects of structural motifs are explored in detail, where the importance of mechanical roles of transmembrane helices, cytoplasmic helices, and loops are discussed. The conformation transitions under complex membrane deformations are predicted, including bending, torsion, cooperativity, patch clamp, and indentation. Compared to atom-based molecular dynamics simulations and elastic network models, the MDeFEM framework is unusually well-suited for simulating complex deformations at large length scales. The versatile hierarchical framework can be further applied to simulate the gating transition of other mechanosensitive channels and other biological processes where mechanical perturbation is important. 10.1529/biophysj.107.128496

On the Construction and Comparison of Difference Schemes

Gilbert Strang — 2008-06-27T20:55:35-00:00

SIAM Journal on Numerical Analysis, Vol. 5, No. 3. (1968), pp. 506-517.

Self-consistent dissipative particle dynamics algorithm

I Pagonabarraga — 2008-06-27T20:54:56-00:00

EPL (Europhysics Letters), Vol. 42, No. 4. (1998), pp. 377-382.

We propose an implementation of dissipative particle dynamics that is free of the inconsistencies that plagued earlier algorithms. The present algorithm satisfies a form of microscopic reversibility. As a consequence, we recover the correct equilibrium properties. Moreover, we can use much larger time steps than previously. We report a detailed comparison between simulated transport properties and the theoretical predictions. We find that the existing theory is only valid under very special conditions. A more general theory is still lacking.

A stochastic Trotter integration scheme for dissipative particle dynamics

M Serrano — 2008-06-27T20:54:13-00:00

Mathematics and Computers in Simulation, Vol. 72, No. 2-6. (9 September 2006), pp. 190-194.

In this article we show in detail the derivation of an integration scheme for the dissipative particle dynamic model (DPD) using the stochastic Trotter formula [G. De Fabritiis, M. Serrano, P. Español, P.V. Coveney, Phys. A 361 (2006) 429]. We explain some subtleties due to the stochastic character of the equations and exploit analyticity in some interesting parts of the dynamics. The DPD-Trotter integrator demonstrates the inexistence of spurious spatial correlations in the radial distribution function for an ideal gas equation of state. We also compare our numerical integrator to other available DPD integration schemes.

Dynamical regimes in the dissipative particle dynamics model

Pep Español — 2008-06-27T20:45:38-00:00

Physical Review E, Vol. 59, No. 6. (1 June 1999), 6340.

Hydrodynamics from dissipative particle dynamics

Pep Español — 2008-06-27T20:44:58-00:00

Physical Review E, Vol. 52, No. 2. (1995), 1734.

Scaling of the time-dependent self-diffusion coefficient and the propagation of hydrodynamic interactions

Pep Español — 2008-06-27T20:44:34-00:00

Physical Review E, Vol. 51, No. 1. (1 January 1995), 803.

Dissipative particle dynamics for a harmonic chain: A first-principles derivation

Pep Español — 2008-06-27T20:44:15-00:00

Physical Review E, Vol. 53, No. 2. (1 February 1996), 1572.

Thermodynamically Admissible Form for Discrete Hydrodynamics

Pep Español — 2008-06-27T20:43:56-00:00

Physical Review Letters, Vol. 83, No. 22. (29 November 1999), 4542.

Thermodynamically consistent mesoscopic fluid particle model

Mar Serrano — 2008-06-27T20:43:37-00:00

Physical Review E, Vol. 64, No. 4. (2001), 046115.

Smoothed dissipative particle dynamics

Pep Español — 2008-06-27T20:43:21-00:00

Physical Review E, Vol. 67, No. 2. (26 February 2003), 026705.

Smoothed particle hydrodynamics model for phase separating fluid mixtures. I. General equations

Cedric Thieulot — 2008-06-27T20:42:55-00:00

Physical Review E (Statistical, Nonlinear, and Soft Matter Physics), Vol. 72, No. 1. (2005)

We present a thermodynamically consistent discrete fluid particle model for the simulation of a recently proposed set of hydrodynamic equations for a phase separating van der Waals fluid mixture [P. Español and C.A.P. Thieulot, J. Chem. Phys. 118, 9109 (2003)]. The discrete model is formulated by following a discretization procedure given by the smoothed particle hydrodynamics (SPH) method within the thermodynamically consistent general equation for the nonequilibrium reversible-irreversible coupling (GENERIC) framework. Each fluid particle carries information on the mass, momentum, energy, and the mass fraction of the different components. The discrete model allows one to simulate nonisothermal dynamic evolution of phase separating fluids with surface tension effects while respecting the first and second laws of thermodynamics exactly.

Shadow mass and the relationship between velocity and momentum in symplectic numerical integration

Jason Gans — 2008-06-27T19:47:51-00:00

Physical Review E, Vol. 61, No. 4. (1 April 2000), 4587.

Molecular simulations of mesoscopic bilayer phases

Marieke Kranenburg — 2008-06-27T19:46:49-00:00

Physical Review E, Vol. 67, No. 6. (18 June 2003), 060901.

Configurational Temperature in Membrane Simulations Using Dissipative Particle Dynamics

MP Allen — 2008-06-27T19:43:35-00:00

J. Phys. Chem. B, Vol. 110, No. 8. (2 March 2006), pp. 3823-3830.

Abstract: The use of excessively long time steps in dissipative particle dynamics simulations may produce simulation artifacts due to the generation of configurations which are not representative of the desired canonical ensemble. The configurational temperature, among other quantities, may be used to assess the extent of the deviation from equilibrium. This paper presents results for simulations of models of water and lipid bilayer membranes to illustrate the nature of the problems.

RSH/Smith-Lemli-Opitz Syndrome: A Multiple Congenital Anomaly/Mental Retardation Syndrome due to an Inborn Error of Cholesterol Biosynthesis

Forbes Porter — 2008-06-27T18:44:44-00:00

Molecular Genetics and Metabolism, Vol. 71, No. 1-2. (September 2000), pp. 163-174.

The RSH/Smith-Lemli-Opitz syndrome (RSH/SLOS) is an autosomal recessive multiple congenital anomaly/mental retardation syndrome caused by an inborn error of cholesterol biosynthesis. The RSH/SLOS phenotypic spectrum is broad; however, typical features include microcephaly, ptosis, a small upturned nose, micrognathia, postaxial polydactaly, second and third toe syndactaly, genital anomalies, growth failure, and mental retardation. RSH/SLOS is due to a deficiency of the 3[beta]-hydroxysterol [Delta]7-reductase, which catalyzes the reduction of 7-dehydrocholesterol (7-DHC) to cholesterol. This inborn error of cholesterol biosynthesis results in elevated serum and tissue 7-DHC levels. The 3[beta]-hydroxysterol [Delta]7-reductase gene (DHCR7) maps to chromosome 11q12-13, and to date 66 different mutations of this gene have been identified in RSH/SLOS patients. Identification of the biochemical basis of RSH/SLOS has led to development of therapeutic regimens based on dietary cholesterol supplementation and has increased our understanding of the role cholesterol plays during embryonic development.

Simulation study of lateral diffusion in lipid-sterol bilayer mixtures

JM Polson — 2008-06-27T18:43:42-00:00

The European Physical Journal E - Soft Matter, Vol. 5, No. 4. (19 July 2001), pp. 485-497.

Abstract: We employ off-lattice Monte Carlo simulations to study lateral diffusion in lipid-sterol bilayers using a two-dimensional model system which has been designed to simulate the experimental phase diagrams of both lipid-cholesterol and lipid-lanosterol systems. We focus on the effects of varying sterol concentration and temperature on the tracer diffusion coefficient, D, which characterizes the lateral motion of single tagged lipids in a bilayer. Generally, we find that increasing the cholesterol concentration suppresses D due to an increased conformational ordering of lipid chains. We argue that this effect competes with an increase in the average free area per lipid, which favours an increase in D. At temperatures close to the main transition temperature, the competition between the two effects leads to intriguing behavior of D. Overall, the model results are in excellent qualitative agreement with available experimental results for lipid-cholesterol mixtures. Additional studies of a model lipid-lanosterol system, for which experimental diffusion results are not available, predict that the presence of lanosterol has a smaller effect than cholesterol on reducing D relative to the pure lipid system. We conclude that the molecular model employed contains the essential features required to describe many of the qualitative features of the lateral diffusion behavior in lipid-sterol systems.

The permeability and the effect of acyl-chain length for phospholipid bilayers containing cholesterol: theory and experiment

E Corvera — 2008-06-27T18:43:12-00:00

Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1107, No. 2. (30 June 1992), pp. 261-270.

The model of Cruzeiro-Hansson et al. (Biochim. Biophys. Acta (1989) 979, 166-1176) for lipid-cholesterol bilayers at low cholesterol concentrations is used to predict the thermodynamic properties and the passive ion permeability of lipid bilayers as a function of acyl-chain length and cholesterol concentration. Numerical simulations based on the Monte Carlo method are used to determine the equilibrium state of the system near the main gel-fluid phase transition. The permeability is calculated using an ansatz which relates the passive permeability to the amount of interfaces formed in the bilayer when cholesterol is present. The model predicts at low cholesterol contents an increase in the membrane permeability in the transition region both for increasing cholesterol concentration and for decreasing chain length at a given value of the reduced temperature. This is in contrast to the case of lipid bilayers containing high cholesterol concentrations where the cholesterol strongly surpresses the permeability. Experimental results for the Na+ permeability of C15PC and DPPC (C16PC) bilayers containing cholesterol are presented which confirm the theoretical predictions at low cholesterol concentrations.

Condensed complexes of cholesterol and phospholipids

Harden Mcconnell — 2008-06-27T18:42:38-00:00

Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1610, No. 2. (10 March 2003), pp. 159-173.

There is overwhelming evidence that lipid bilayer regions of animal cell membranes are in a liquid state. Quantitative models of these bilayer regions must then be models of liquids. These liquids are highly non-ideal. For example, it has been known for more than 75 years that mixtures of cholesterol and certain phospholipids undergo an area contraction or condensation in lipid monolayers at the air-water interface. In the past 3 years, a thermodynamic model of "condensed complexes" has been proposed to account for this non-ideal behavior. Here we give an overview of the model, its relation to other models, and to modern views of the properties of animal cell membranes.

Cholesterol Rules: DIRECT OBSERVATION OF THE COEXISTENCE OF TWO FLUID PHASES IN NATIVE PULMONARY SURFACTANT MEMBRANES AT PHYSIOLOGICAL TEMPERATURES

Bernardino — 2008-06-27T18:42:05-00:00

J. Biol. Chem., Vol. 279, No. 39. (24 September 2004), pp. 40715-40722.

Pulmonary surfactant, the lipid-protein material that stabilizes the respiratory surface of the lungs, contains approximately equimolar amounts of saturated and unsaturated phospholipid species and significant proportions of cholesterol. Such lipid composition suggests that the membranes taking part in the surfactant structures could be organized heterogeneously in the form of inplane domains, originating from particular distributions of specific proteins and lipids. Here we report novel results concerning the lateral organization of bilayer membranes made of native pulmonary surfactant where the coexistence of two distinct micrometer sized fluid phases (fluid ordered and fluid disordered-like phases) is observed at physiological temperatures by using fluorescence microscopy and atomic force microscopy. Additional experiments using fluorescent-labeled proteins SP-B and SP-C show that at physiological temperatures these hydrophobic proteins are located exclusively in the fluid disordered-like phase. Most interestingly, the microscopic coexistence of fluid phases is maintained up to 37.5 degreesC, where most fluid ordered phases melt. This observation suggests that the particular composition of this material is naturally designed to be at the "edge" of a lateral structure transition under physiological conditions, likely providing particular structural and dynamic properties for its mechanical function. The observed lateral structure in native pulmonary surfactant membranes is dramatically affected by the extraction of cholesterol, an effect not observed upon extraction of the surfactant proteins. Furthermore, the spreading properties of the native surfactant material at the air-liquid interface were also greatly affected by cholesterol extraction, suggesting a connection between the observed lateral structure and a physiologically relevant function of the material. We suggest that the particular lipid composition of surfactant could be finely tuned to provide, under physiological conditions, a structural scaffold for surfactant proteins to act at appropriate local densities and lipid composition. 10.1074/jbc.M404648200

Role of cholesterol in lipid raft formation: lessons from lipid model systems

John Silvius — 2008-06-27T18:41:34-00:00

Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1610, No. 2. (10 March 2003), pp. 174-183.

Biochemical and cell-biological experiments have identified cholesterol as an important component of lipid [`]rafts' and related structures (e.g., caveolae) in mammalian cell membranes, and membrane cholesterol levels as a key factor in determining raft stability and organization. Studies using cholesterol-containing bilayers as model systems have provided important insights into the roles that cholesterol plays in determining lipid raft behavior. This review will discuss recent progress in understanding two aspects of lipid-cholesterol interactions that are particularly relevant to understanding the formation and properties of lipid rafts. First, we will consider evidence that cholesterol interacts differentially with different membrane lipids, associating particularly strongly with saturated, high-melting phospho- and sphingolipids and particularly weakly with highly unsaturated lipid species. Second, we will review recent progress in reconstituting and directly observing segregated raft-like (liquid-ordered) domains in model membranes that mimic the lipid compositions of natural membranes incorporating raft domains.

The Effect of Sterol Structure on Membrane Lipid Domains Reveals How Cholesterol Can Induce Lipid Domain Formation

X Xu — 2008-06-27T18:40:48-00:00

Biochemistry, Vol. 39, No. 5. (8 February 2000), pp. 843-849.

Abstract: Detergent-insoluble membrane domains, enriched in saturated lipids and cholesterol, have been implicated in numerous biological functions. To understand how cholesterol promotes domain formation, the effect of various sterols and sterol derivatives on domain formation in mixtures of the saturated lipid dipalmitoylphosphatidylcholine (DPPC) and a fluorescence quenching analogue of an unsaturated lipid was compared. Quenching measurements demonstrated that several sterols (cholesterol, dihydrocholesterol, epicholesterol, and 25-hydroxycholesterol) promote formation of DPPC-enriched domains. Other sterols and sterol derivatives had little effect on domain formation (cholestane and lanosterol) or, surprisingly, strongly inhibit it (coprostanol, androstenol, cholesterol sulfate, and 4-cholestenone). The effect of sterols on domain formation was closely correlated with their effects on DPPC insolubility. Those sterols that promoted domain formation increased DPPC insolubility, whereas those sterols that inhibit domain formation decreased DPPC insolubility. The effects of sterols on the fluorescence polarization of diphenylhexatriene incorporated into DPPC-containing vesicles were also correlated with sterol structure. These experiments indicate that the effect of sterol on the ability of saturated lipids to form a tightly packed (i.e., tight in the sense that the lipids are closely packed with one another) and ordered state is the key to their effect on domain formation. Those sterols that promote tight packing of saturated lipids promote domain formation, while those sterols that inhibited tight packing of saturated lipids inhibited domain formation. The ability of some sterols to inhibit domain formation (i.e., act as "anti-cholesterols") should be a valuable tool for examining domain formation and properties in cells.

Cholesterol-phospholipid interactions, the liquid-ordered phase and lipid rafts in model and biological membranes

Todd Mcmullen — 2008-06-27T18:40:20-00:00

Current Opinion in Colloid & Interface Science, Vol. 8, No. 6. (April 2004), pp. 459-468.

The existence of relatively large and long-lived detergent-insoluble, sphingolipid- and cholesterol-enriched, liquid-ordered lipid raft domains in the plasma membranes of eukaryotic cells has become widely accepted. However, we believe that the evidence for their existence is not compelling despite extensive work on both lipid bilayer model and biological membranes. We review here the results of recent studies, which in our view call into question the existence of lipid rafts in membranes, at least in the form commonly depicted.

From Lanosterol to Cholesterol: Structural Evolution and Differential Effects on Lipid Bilayers

Ling Miao — 2008-06-27T18:39:26-00:00

Biophys. J., Vol. 82, No. 3. (1 March 2002), pp. 1429-1444.

Cholesterol is an important molecular component of the plasma membranes of mammalian cells. Its precursor in the sterol biosynthetic pathway, lanosterol, has been argued by Konrad Bloch (Bloch, K. 1965. Science. 150:19-28; 1983. CRC Crit. Rev. Biochem. 14:47-92; 1994. Blonds in Venetian Paintings, the Nine-Banded Armadillo, and Other Essays in Biochemistry. Yale University Press, New Haven, CT.) to also be a precursor in the molecular evolution of cholesterol. We present a comparative study of the effects of cholesterol and lanosterol on molecular conformational order and phase equilibria of lipid-bilayer membranes. By using deuterium NMR spectroscopy on multilamellar lipid-sterol systems in combination with Monte Carlo simulations of microscopic models of lipid-sterol interactions, we demonstrate that the evolution in the molecular chemistry from lanosterol to cholesterol is manifested in the model lipid-sterol membranes by an increase in the ability of the sterols to promote and stabilize a particular membrane phase, the liquid-ordered phase, and to induce collective order in the acyl-chain conformations of lipid molecules. We also discuss the biological relevance of our results, in particular in the context of membrane domains and rafts.

Why do worms need cholesterol?

TV Kurzchalia — 2008-06-24T10:35:50-00:00

Nature cell biology, Vol. 5, No. 8. (August 2003), pp. 684-688.

Cholesterol is a structural component of animal membranes that influences fluidity, permeability and formation of lipid microdomains. It is also a precursor to signalling molecules, including mammalian steroid hormones and insect ecdysones. The nematode Caenorhabditis elegans requires too little cholesterol for it to have a major role in membrane structure. Instead, its most probable signalling functions are to control molting and induce a specialized non-feeding larval stage, although no cholesterol-derived signalling molecule has yet been identified for these or any other functions.

Lipids do influence protein function--the hydrophobic matching hypothesis revisited

Morten Jensen — 2008-06-27T18:37:46-00:00

Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1666, No. 1-2. (3 November 2004), pp. 205-226.

A topical review of the current state of lipid-protein interactions is given with focus on the physical interactions between lipids and integral proteins in lipid-bilayer membranes. The concepts of hydrophobic matching and curvature stress are revisited in light of recent data obtained from experimental and theoretical studies which demonstrate that not only do integral proteins perturb the lipids, but the physical state of the lipids does also actively influence protein function. The case of the trans-membrane water-channel protein aquaporin GlpF from E. coli imbedded in lipid-bilayer membranes is discussed in some detail. Numerical data obtained from Molecular Dynamics simulations show on the one side that the lipid bilayer adapts to the channel by a hydrophobic matching condition which reflects the propensity of the lipid molecules for forming curved structures. On the other side, it is demonstrated that the transport function of the channel is modulated by the matching condition and/or the curvature stress in a lipid-specific manner.

What's so special about cholesterol?

Ole Mouritsen — 2008-06-27T18:37:06-00:00

Lipids, Vol. 39, No. 11. (17 November 2004), pp. 1101-1113.

Abstract Cholesterol (or other higher sterols such as ergosterol and phytosterols) is universally present in large amounts (20–40 mol%) in eukaryotic plasma membranes, whereas it is universally absent in the membranes of prokaryotes. Cholesterol has a unique ability to increase lipid order in fluid membranes while maintaining fluidity and diffusion rates. Cholesterol imparts low permeability barriers to lipid membranes and provides for large mechanical coherence. A short topical review is given of these special properties of cholesterol in relation to the structure of membranes, with results drawn from a variety of theoretical and experimental studies. Particular focus is put on cholesterol's ability to promote a special membrane phase, the liquidordered phase, which is unique for cholesterol (and other higher sterols like ergosterol) and absent in membranes containing the cholesterol precursor lanosterol. Cholesterol's role in the formation of special membrane domains and so-called rafts is discussed.

A Quantitative Coarse-Grain Model for Lipid Bilayers

M Orsi — 2008-01-25T12:57:38-00:00

J. Phys. Chem. B, Vol. 112, No. 3. (24 January 2008), pp. 802-815.

Abstract: A simplified particle-based computer model for hydrated phospholipid bilayers has been developed and applied to quantitatively predict the major physical features of fluid-phase biomembranes. Compared with available coarse-grain methods, three novel aspects are introduced. First, the main electrostatic features of the system are incorporated explicitly via charges and dipoles. Second, water is accurately (yet efficiently) described, on an individual level, by the soft sticky dipole model. Third, hydrocarbon tails are modeled using the anisotropic Gay-Berne potential. Simulations are conducted by rigid-body molecular dynamics. Our technique proves 2 orders of magnitude less demanding of computational resources than traditional atomic-level methodology. Self-assembled bilayers quantitatively reproduce experimental observables such as electron density, compressibility moduli, dipole potential, lipid diffusion, and water permeability. The lateral pressure profile has been calculated, along with the elastic curvature constants of the Helfrich expression for the membrane bending energy; results are consistent with experimental estimates and atomic-level simulation data. Several of the results presented have been obtained for the first time using a coarse-grain method. Our model is also directly compatible with atomic-level force fields, allowing mixed systems to be simulated in a multiscale fashion.

Identification of Possible Sources of Nanotoxicity from Carbon Nanotubes Inserted into Membrane Bilayers Using Membrane Interaction Quantitative Structure−Activity Relationship Analysis

Jianzhong Liu — 2008-06-27T18:33:28-00:00

Chem. Res. Toxicol., Vol. 21, No. 2. (18 February 2008), pp. 459-466.

ABSTRACT Four possible sources of cellular toxicity due to the insertion of a carbon nanotube into a dimyristoylphosphatidylcholine (DMPC) membrane bilayer were explored using the membrane interaction quantitative structureactivity relationship methodology. Comparisons of (i) the structural organization of the membrane bilayer, (ii) dynamical features of the membrane bilayer, and (iii) transport of small polar molecules across the membrane bilayer were carried out with, and without, a carbon nanotube inserted into the bilayer. A fourth study was performed to determine how the transport of solvated ions through the inserted nanotube might alter the structure of the membrane bilayer. Two large changes in the bilayer occur due to insertion of the carbon nanotube. First, there is an alteration in the packing of the DMPC bilayer molecules, which extends at least 18 Å from the nanotube, and includes the creation of a relatively open, unoccupied cylindrical ring of 24 Å thickness directly around the nanotube. Second, the same bilayer structure, which undergoes the change in structural organization, also becomes much more rigid than when the nanotube is not inserted. Solvated calcium ions are predicted to preferentially transport through the inserted nanotube as compared to hydrated sodium ions, but the solvated calcium ion also produces an alteration in the local bilayer structure as it passes through the nanotube. The total diffusion coefficient of ethanol through the membrane bilayer increases by about 35% in the presence of the inserted nanotube. Urea and caffeine also undergo increases in their diffusion coefficients for transport through the bilayer, due to the inserted nanotube, but these increases are less than that of ethanol. Each of the three penetrants also diffuses more directly through the membrane bilayer in the presence of the nanotube, especially caffeine and urea.

Counterion Distribution and ζ-Potential in PAMAM Dendrimer

Prabal Maiti — 2008-06-27T18:32:31-00:00

Macromolecules (10 June 2008)

Abstract: Using several hundred nanosecond long fully atomistic molecular dynamics simulations, we investigate the monomer and counterion local concentrations in poly amido amide (PAMAM) dendrimer systems for various generations at neutral pH. We also calculate the ¶ potential as a function of dendrimer generation. It is found that the ¶ potential increases with dendrimer generation, but slowly at high generation. The ¶ potential behavior is remarkably well reproduced when employing Monte Carlo simulations and the PoissonBoltzmann theory for colloidal particles with size and effective charge of the dendrimer as relevant input parameters from the fully atomistic simulations.

An Equilibrium Method for Continuous-Flow Cell Sorting Using Dielectrophoresis

MD Vahey — 2008-04-07T08:14:16-00:00

Anal. Chem. (26 March 2008)

Abstract: Separations represent a fundamental unit operation in biology and biotechnology. Commensurate with their importance is the diversity of methods that have been developed for performing them. One important class of separations are equilibrium gradient methods, wherein a medium with some type of spatial nonuniformity is combined with a force field to focus particles to equilibrium positions related to those particles' intrinsic properties. A second class of techniques that is nonequilibrium exploits labels to sort particles based upon their extrinsic properties. While equilibrium techniques such as iso-electric focusing (IEF) have become instrumental within analytical chemistry and proteomics, cell separations predominantly rely upon the second, label-based class of techniques, exemplified by fluorescence-activated cell sorting (FACS) and magnetic-activated cell sorting (MACS). To extend the equilibrium techniques available for separating cells, we demonstrate the first implementation of a new microfluidic equilibrium separation method, which we call isodielectric separation (IDS), for sorting cells based upon electrically distinguishable phenotypes. IDS is analogous to isoelectric focusing, except instead of separating amphoteric molecules in a pH gradient using electrophoresis, we separate cells and particles in an electrical conductivity gradient using dielectrophoresis. IDS leverages many of the advantages of microfluidics and equilibrium gradient separation methods to create a device that is continuous-flow, capable of parallel separations of multiple (>2) subpopulations from a heterogeneous background, and label-free. We demonstrate the separation of polystyrene beads based upon surface conductance as well as sorting nonviable from viable cells of the budding yeast Saccharomyces cerevisiae.

Differential Effects of Cholesterol and its Immediate Biosynthetic Precursors on Membrane Organization

Sandeep:paila Shrivastava — 2008-04-30T00:10:17-00:00

Biochemistry (29 April 2008)

Abstract: Cholesterol is the most representative sterol present in vertebrate membranes and is the end product of the long and multistep sterol biosynthetic pathway. 7-Dehydrocholesterol (7-DHC) and desmosterol are the immediate biosynthetic precursors of cholesterol in the Kandutsch-Russell and Bloch pathway. In this article, we have monitored the effect of cholesterol and its two immediate biosynthetic precursors on biophysical and dynamic properties of fluid and gel phase membranes. Toward this goal, we have used fluorescent membrane probes, DPH and TMA-DPH, and the hydrophobic probe, pyrene. Our results using these probes show that although both 7-DHC and desmosterol differ with cholesterol in one double bond, they exhibit differential effects on membrane organization and dynamics. Importantly, we show that the effect of cholesterol and desmosterol on membrane organization and dynamics is similar in most cases, while 7-DHC has a considerably different effect. This demonstrates that the position of the double bond in sterols is an important determinant in maintaining membrane order and dynamics. These results assume relevance since the accumulation of cholesterol precursors have been reported to result in severe pathological conditions.

The MARTINI Coarse-Grained Force Field: Extension to Proteins

Luca Monticelli — 2008-04-16T13:18:43-00:00

J. Chem. Theory Comput. (16 April 2008)

Abstract: Many biologically interesting phenomena occur on a time scale that is too long to be studied by atomistic simulations. These phenomena include the dynamics of large proteins and self-assembly of biological materials. Coarse-grained (CG) molecular modeling allows computer simulations to be run on length and time scales that are 23 orders of magnitude larger compared to atomistic simulations, providing a bridge between the atomistic and the mesoscopic scale. We developed a new CG model for proteins as an extension of the MARTINI force field. Here, we validate the model for its use in peptide-bilayer systems. In order to validate the model, we calculated the potential of mean force for each amino acid as a function of its distance from the center of a dioleoylphosphatidylcholine (DOPC) lipid bilayer. We then compared amino acid association constants, the partitioning of a series of model pentapeptides, the partitioning and orientation of WALP23 in DOPC lipid bilayers and a series of KALP peptides in dimyristoylphosphatidylcholine and dipalmitoylphosphatidylcholine (DPPC) bilayers. A comparison with results obtained from atomistic models shows good agreement in all of the tests performed. We also performed a systematic investigation of the partitioning of five series of polyalanineleucine peptides (with different lengths and compositions) in DPPC bilayers. As expected, the fraction of peptides partitioned at the interface increased with decreasing peptide length and decreasing leucine content, demonstrating that the CG model is capable of discriminating partitioning behavior arising from subtle differences in the amino acid composition. Finally, we simulated the concentration-dependent formation of transmembrane pores by magainin, an antimicrobial peptide. In line with atomistic simulation studies, disordered toroidal pores are formed. In conclusion, the model is computationally efficient and effectively reproduces peptidelipid interactions and the partitioning of amino acids and peptides in lipid bilayers.

Effects of Carboxylate-Modified, “Green” Inulin Biopolymers on the Crystal Growth of Calcium Oxalate

Bora Akın — 2008-06-27T18:27:39-00:00

Cryst. Growth Des., Vol. 8, No. 6. (4 June 2008), pp. 1997-2005.

Abstract: In this work, the effect of a biodegradable, environmentally friendly polysaccharide-based polycarboxylate, carboxymethyl inulin (CMI), on the crystal growth kinetics of calcium oxalate was studied at 37 °C. CMI is produced by carboxymethylation of inulin, the latter extracted from chicory roots. The spontaneous crystallization method was utilized to investigate the crystallization kinetics of calcium oxalate (CaC2O4, CaOx). The experimental results show that the retardation in mass transport in the growth process is controlled by the carboxylation degree of CMI and also its concentration. Our studies also indicate that polymers were effective in directing calcium oxalate crystallization from calcium oxalate monohydrate (COM) to calcium oxalate dihydrate (COD). Comparisons with the effects of polyacrylate (PAA) additive, which was also included in our experiments, show that PAA is a more effective inhibitor than CMI-15 and CMI-20, and comparable to CMI-25.

Monitoring Biological Membrane-Potential Changes: A CI QM/MM Study

CF Rusu — 2008-03-03T12:16:17-00:00

J. Phys. Chem. B, Vol. 112, No. 8. (28 February 2008), pp. 2445-2455.

Abstract: In recent decades, new less-invasive, nonlinear optical methods have been proposed and optimized for monitoring fast physiological processes in biological cells. One of these methods allows the action potential (AP) in cardiomyocytes or neurons to be monitored by means of second-harmonic generation (SHG). We now present the first, to our knowledge, simulations of the dependency of the intensity of the second harmonic (ISHG) on variations of the transmembrane potential (TMP) in a cardiomyocyte during an action potential (AP). For this, an amphiphilic potential-sensitive styryl dye molecule with nonlinear optical properties was embedded in a dipalmitoylphosphatidylcholine (DPPC) bilayer, replacing one of the phospholipid molecules. External electrical fields with different strengths were applied across the membrane to simulate the AP of a heart-muscle cell. We used a combined classical/quantum mechanical approach to model the structure and the spectroscopic properties of the embedded chromophore. Two 10 ns molecular dynamics (MD) simulations provided input geometries for semiempirical molecular orbital (QM/MM) single-point configuration interaction (CI) calculations, which were used to calculate the wavelengths and oscillator strengths of electronic transitions in the di-8-ANEPPS dye molecule. The results were then used in a sum-over-states treatment to calculate the second-order hyperpolarizability. The square of the hyperpolarizability scales with the intensity of the second harmonic, which is used to monitor the action potentials of cardiomyocytes experimentally. Thus, we computed changes in the intensity of the second harmonic (ISHG) as function of TMP changes. Our results agree well with experimental measurements.

Energetics of Cholesterol Transfer between Lipid Bilayers.

Zhancheng Zhang — 2008-03-03T04:01:25-00:00

J Phys Chem B (29 February 2008)

It is believed that natural biological membranes contain domains of lipid ordered phase enriched in cholesterol and sphingomyelin. Although the existence of these domains, called lipid rafts, is still not firmly established for natural membranes, direct microscopic observations and phase diagrams obtained from the study of three-component mixtures containing saturated phospholipids, unsaturated phospholipids, and cholesterol demonstrate the existence of lipid rafts in synthetic membranes. The presence of the domains or rafts in these membranes is often ascribed to the preferential interactions between cholesterol and saturated phospholipids, for example, between cholesterol and sphingomyelin. In this work, we calculate, using molecular dynamics computer simulation technique, the free energy of cholesterol transfer from the bilayer containing unsaturated phosphatidylcholine lipid molecules to the bilayer containing sphingomyelin molecules and find that the affinity of cholesterol to sphingomyelin is higher. Our calculations of the free-energy components, energy and entropy, show that cholesterol transfer is exothermic and promoted by the favorable change in the lipid-lipid interactions near cholesterol and not by the favorable energy of cholesterol-sphingomyelin interaction, as assumed previously.

Constrained Isothermal-Isobaric Molecular Dynamics with Full Atomic Virial

G Ciccotti — 2008-06-27T18:19:58-00:00

J. Phys. Chem. B, Vol. 105, No. 28. (19 July 2001), pp. 6710-6715.

Abstract: We consider the isobaric-isothermal molecular dynamics method in a system subject to a set of holonomic constraints with a full atomic description of the virial. By applying the non-Hamiltonian statistical mechanical theory recently developed by Tuckerman et al. [Tuckerman, M. E.; Mundy, C. J.; Martyna, G. J. Europhys. Lett. 1999, 45, 149], the Kneller-Mülders equations [Kneller, G. R.; Mülders, T. Phys. Rev. E 1996, 54, 6825] are analyzed, and it is determined that they sample the desired ensemble only under certain circumstances. In general, a bias arising from the conservation of total momentum needs to be corrected. Thus, a new set of equations of motion is presented and the phase space generated by these equations is shown to be correct under all circumstances.

Structure of Aqueous Proline via Parallel Tempering Molecular Dynamics and Neutron Diffraction

RZ Troitzsch — 2008-06-27T18:19:26-00:00

J. Phys. Chem. B, Vol. 111, No. 28. (19 July 2007), pp. 8210-8222.

Abstract: The structure of aqueous L-proline amino acid has been the subject of much debate centering on the validity of various proposed models, differing widely in the extent to which local and long-range correlations are present. Here, aqueous proline is investigated by atomistic, replica exchange molecular dynamics simulations, and the results are compared to neutron diffraction and small angle neutron scattering (SANS) data, which have been reported recently (McLain, S.; Soper, A.; Terry, A.; Watts, A. J. Phys. Chem. B 2007, 111, 4568). Comparisons between neutron experiments and simulation are made via the static structure factor S(Q) which is measured and computed from several systems with different H/D isotopic compositions at a concentration of 1:20 molar ratio. Several different empirical water models (TIP3P, TIP4P, and SPC/E) in conjunction with the CHARMM22 force field are investigated. Agreement between experiment and simulation is reasonably good across the entire Q range although there are significant model-dependent variations in some cases. In general, agreement is improved slightly upon application of approximate quantum corrections obtained from gas-phase path integral simulations. Dimers and short oligomeric chains formed by hydrogen bonds (frequently bifurcated) coexist with apolar (hydrophobic) contacts. These emerge as the dominant local motifs in the mixture. Evidence for long-range association is more equivocal: No long-range structures form spontaneously in the MD simulations, and no obvious low-Q signature is seen in the SANS data. Moreover, associations introduced artificially to replicate a long-standing proposed mesoscale structure for proline correlations as an initial condition are annealed out by parallel tempering MD simulations. However, some small residual aggregates do remain, implying a greater degree of long-range order than is apparent in the SANS data.

Understanding Modern Molecular Dynamics: Techniques and Applications

ME Tuckerman — 2008-01-11T15:51:09-00:00

J. Phys. Chem. B, Vol. 104, No. 2. (20 January 2000), pp. 159-178.

Abstract: Recent advances in molecular dynamics methodology have made it possible to study routinely the microscopic details of chemical processes in the condensed phase using high-speed computers. Thus, it is timely and useful to provide a pedagogical treatment of the theoretical and numerical aspects of modern molecular dynamics simulation techniques and to show several applications that illustrate the capability of these approaches. First, the standard Newtonian or Hamiltonian dynamics based method is presented followed by a discussion of theoretical advances related to non-Hamiltonian molecular dynamics. Examples of non-Hamiltonian molecular dynamics schemes capable of generating the canonical and isothermal-isobaric ensemble are analyzed. Next, the novel Liouville operator factorization approach to numerical integration is reviewed. The power and utility of this new technique are contrasted to more basic methods, particularly, in the development of multiple time scale and non-Hamiltonian integrators. Since the results of molecular dynamics simulations depend on the interparticle interactions employed in the calculations, modern empirical force fields and ab initio molecular dynamics approaches are discussed. An example calculation combining an empirical force field and novel molecular dynamics methods, the mutant T4 lysozyme M61 in water, will be presented. The combination of electronic structure with classical dynamics, the so called ab initio molecular dynamics method, will be described and an application to the structure of liquid ammonia discussed. Last, it will then be shown how the classical molecular dynamics methods can be adapted for quantum calculations using the Feynman path integral formulation of statistical mechanics. An application, employing both path integrals and ab initio molecular dynamics, to an excess proton in water will be presented.

Structure and internal dynamics of a side chain liquid crystalline polymer in various phases by molecular dynamics simulations: A step towards coarse graining

Jaroslav Ilnytskyi — 2008-06-27T16:02:49-00:00

The Journal of Chemical Physics, Vol. 126, No. 17. (2007)

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Plasma membrane-associated proteins are clustered into islands attached to the cytoskeleton.

Björn F Lillemeier — 2006-12-13T15:19:53-00:00

Proc Natl Acad Sci U S A (4 December 2006)

Although much evidence suggests that the plasma membrane of eukaryotic cells is not homogenous, the precise architecture of this important structure has not been clear. Here we use transmission electron microscopy of plasma membrane sheets and specific probes to show that most or all plasma membrane-associated proteins are clustered in cholesterol-enriched domains ("islands") that are separated by "protein-free" and cholesterol-low membrane. These islands are further divided into subregions, as shown by the localization of "raft" and "non-raft" markers to specific areas. Abundant actin staining and inhibitor studies show that these structures are connected to the cytoskeleton and at least partially depend on it for their formation and/or maintenance.

Coupled composition-deformation phase-field method for multicomponent lipid membranes

Chloe Funkhouser — 2008-04-21T10:38:12-00:00

Physical Review E (Statistical, Nonlinear, and Soft Matter Physics), Vol. 76, No. 1. (2007)

We present a method for modeling phase transitions and morphological evolution of binary lipid membranes with approximately planar geometries. The local composition and the shape of the membrane are coupled through composition-dependent spontaneous curvature in a Helfrich free energy. The evolution of the composition field is described by a Cahn-Hilliard-type equation, while shape changes are described by relaxation dynamics. Our method explicitly treats the full nonlinear form of the geometrical scalars, tensors, and differential operators associated with the curved shape of the membrane. The model is applied to examine morphological evolution and stability of lipid membranes initialized in a variety of compositional and geometric configurations. Specifically, we investigate the dynamics of systems which have a lamellar structure as their lowest energy state. We find that evolution is very sensitive to initial conditions; only membranes with sufficiently large lamellar-type compositional perturbations or ripple-type shape perturbations in their initial configuration can deterministically evolve into a lamellar equilibrium morphology. We also observe that rigid topographical surface patterns have a strong effect on the phase separation and compositional evolution in these systems.

Modulated phases in multicomponent fluid membranes

Sunil Kumar — 2008-06-26T18:36:31-00:00

Physical Review E, Vol. 60, No. 4. (1 October 1999), 4610.

Coupling Field Theory with Mesoscopic Dynamical Simulations of Multicomponent Lipid Bilayers

Liam Mcwhirter — 2008-06-26T18:36:13-00:00

Biophys. J., Vol. 87, No. 5. (1 November 2004), pp. 3242-3263.

A method for simulating a two-component lipid bilayer membrane in the mesoscopic regime is presented. The membrane is modeled as an elastic network of bonded points; the spring constants of these bonds are parameterized by the microscopic bulk modulus estimated from earlier atomistic nonequilibrium molecular dynamics simulations for several bilayer mixtures of DMPC and cholesterol. The modulus depends on the composition of a point in the elastic membrane model. The dynamics of the composition field is governed by the Cahn-Hilliard equation where a free energy functional models the coupling between the composition and curvature fields. The strength of the bonds in the elastic network are then modulated noting local changes in the composition and using a fit to the nonequilibrium molecular dynamics simulation data. Estimates for the magnitude and sign of the coupling parameter in the free energy model are made treating the bending modulus as a function of composition. A procedure for assigning the remaining parameters in the free energy model is also outlined. It is found that the square of the mean curvature averaged over the entire simulation box is enhanced if the strength of the bonds in the elastic network are modulated in response to local changes in the composition field. We suggest that this simulation method could also be used to determine if phase coexistence affects the stress response of the membrane to uniform dilations in area. This response, measured in the mesoscopic regime, is already known to be conditioned or renormalized by thermal undulations. 10.1529/biophysj.104.045716

Nonequilibrium Raftlike Membrane Domains under Continuous Recycling

Matthew Turner — 2008-06-26T18:35:52-00:00

Physical Review Letters, Vol. 95, No. 16. (2005)

We present a model for the kinetics of spontaneous membrane domain (raft) assembly that includes the effect of membrane recycling ubiquitous in living cells. We show that domains can have a broad power-law distribution with an average radius that scales with the 1/4 power of the domain lifetime when the line tension at the domain edges is large. For biologically reasonable recycling and diffusion rates, the average domain radius is in the tens of nm range, consistent with observations. This represents one possible link between signaling (involving rafts) and traffic (recycling) in cells. Finally, we present evidence that suggests that the average raft size may be the same for all scale-free recycling schemes.

Direct Observation of Lipid Domains in Free-Standing Bilayers Using Two-Photon Excitation Fluorescence Microscopy

Luis Bagatolli — 2008-06-26T18:35:35-00:00

Journal of Fluorescence, Vol. 11, No. 3. (2001), pp. 141-160.

The direct observation of temperature-dependent lipid phase equilibria, using two-photon excitation fluorescence microscopy on giant unilamellar vesicles (GUVs) composed of different lipid mixtures, provides novel information about the physical characteristics of lipid domain coexistence. Physical characteristics such as the shape, size, and time evolution of different lipid domains are not directly accessible from the traditional experimental approaches that employ either small and large unilamellar vesicles or multilamellar vesicles. In this review article, we address the most relevant findings reported from our laboratory regarding the direct observation of lipid domain coexistence at the level of single vesicles in artificial and natural lipid mixtures. In addition, key points concerning our experimental approach will be discussed. The unique advantages of the fluorescent probe 6-dodecanoyl-2-dimethylaminonaphthalene (LAURDAN) under two-photon excitation fluorescence microscopy is particularly addressed, especially, the possibility of obtaining information on the phase state of different lipid domains directly from the fluorescent images.