Effects of Cholesterol on the Thermodynamics and Kinetics of Passive Transport of Water through Lipid Membranes

Issack, Bilkiss B.; Peslherbe, Gilles H.

doi:10.1021/jp510497r

Cited by 45 publications

(51 citation statements)

References 78 publications

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“…This observed significant increase of the free energy barrier to transfer water through bilayer with the presence of cholesterol results in a decrease in water permeability. 50,51 Figure 5. Electron density profiles for the oxygen atoms in the oxidized lipid hydrocarbon chains with and without α-toc, and for the hydroxyl groups of α-toc in 50% 12-al and 9-al bilayers.…”

Section: Resultsmentioning

confidence: 99%

Alpha-tocopherol inhibits pore formation in oxidized bilayers

Boonnoy

Karttunen

Wong-ekkabut

2017

Phys. Chem. Chem. Phys.

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ABSTRACT:In biological membranes, alpha-tocopherols (α-toc; vitamin E) protect polyunsaturated lipids from free radicals. Although the interactions of α-toc with nonoxidized lipid bilayers have been studied, their on oxidized bilayers remain unknown. In this study, atomistic molecular dynamics (MD) simulations of oxidized lipid bilayers were performed with varying concentrations of α-toc. Bilayers with 1-palmitoyl-2-lauroyl-sn-glycero-3-phosphocholine (PLPC) lipids and its aldehyde derivatives at 1:1 ratio were studied. Our simulations show that oxidized lipids self-assemble into aggregates with a water pore rapidly developing across the lipid bilayer. The free energy of transporting an α-toc molecule in a lipid bilayer suggests that α-tocs can passively adsorb into the bilayer. When α-toc molecules were present at low concentrations in bilayers containing oxidized lipids, the formation of water pores was slowed down. At high α-toc concentrations, no pores were observed. Based on the simulations, we propose that the mechanism of how α-toc inhibits pore formation in bilayers with oxidized lipids is the following: α-tocs trap the polar groups of the oxidized lipids at the membrane-water interface resulting in a decreased probability for the oxidized lipids to reach contact with the two leaflets and initiate pore formation. This demonstrates that α-toc molecules not only protect the bilayer from oxidation but also help to stabilize the bilayer after lipid peroxidation occurs. These results will help in designing more efficient molecules to protect membranes from oxidative stress.Biological membranes serve as a partition between cells and their environment. Under oxidative stress, unsaturated lipids present in cell membranes may become exposed to attacks by free radicals, that is, oxidation. Oxidation transforms some of the membrane lipids to oxidized ones such as hydroperoxide and aldehyde lipids. 1,2It has also been suggested that internal, that is intra-leaflet, oxidation may be important in altering bilayer properties. 3Lipid peroxidation is an important mechanism of cell membrane damage. [4][5][6] Previous experiments and computer simulations 4,[7][8][9][10][11][12][13][14] have demonstrated how oxidized lipids disturb and deform bilayers. The polar chains in oxidized lipids are energetically unfavorable to stay in the bilayer's interior resulting in the reversal of the polar lipid chain to the bilayer interface. 4,11,15,16 This reversal causes major changes in bilayer properties such as increase of area per lipid, bilayer thinning, decrease of lipid tail order parameter, and increase in water permeability. 4,12,[15][16][17][18] Recently, we performed MD simulations of lipid bilayers with oxidized lipids at high concentrations. Two major oxidized lipid species including hydroperoxide and aldehyde were studied. The results showed that only aldehyde lipids were able to induce pore formation across a PLPC lipid bilayer and cause significant bilayer deformation. 13,15α-toc is well-known as an efficient antioxidant ...

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Section: Resultsmentioning

confidence: 99%

Alpha-tocopherol inhibits pore formation in oxidized bilayers

Boonnoy

Karttunen

Wong-ekkabut

2017

Phys. Chem. Chem. Phys.

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“…An approximate estimate of the diffusion was calculated from the expression in Equation (3) (Issack and Peslherbe, 2015; Woolf and Roux, 1994):

D (z = true〈 z true〉) = \frac{v a r (z)}{τ_{z}}

where < z > is the center of restraint in the umbrella sampling simulations, var( z ) is the variance of z during the simulation, and τ z is the correlation time of the time series of z . The largest error in the estimation of D ( z ) lies in the calculation of τ z (Hummer, 2005; Issack and Peslherbe, 2015).…”

Section: Methodsmentioning

confidence: 99%

“…The largest error in the estimation of D ( z ) lies in the calculation of τ z (Hummer, 2005; Issack and Peslherbe, 2015). To reduce the noise in the estimate of D (z), diffusion was estimated from the full simulation without any block averaging, and thus the uncertainty was calculated only from the series in the two leaflets.…”

Section: Methodsmentioning

confidence: 99%

Sphingolipids contribute to acetic acid resistance in Zygosaccharomyces bailii

Lindahl

Genheden

Eriksson

et al. 2015

Biotech & Bioengineering

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Lignocellulosic raw material plays a crucial role in the development of sustainable processes for the production of fuels and chemicals. Weak acids such as acetic acid and formic acid are troublesome inhibitors restricting efficient microbial conversion of the biomass to desired products. To improve our understanding of weak acid inhibition and to identify engineering strategies to reduce acetic acid toxicity, the highly acetic‐acid‐tolerant yeast Zygosaccharomyces bailii was studied. The impact of acetic acid membrane permeability on acetic acid tolerance in Z. bailii was investigated with particular focus on how the previously demonstrated high sphingolipid content in the plasma membrane influences acetic acid tolerance and membrane permeability. Through molecular dynamics simulations, we concluded that membranes with a high content of sphingolipids are thicker and more dense, increasing the free energy barrier for the permeation of acetic acid through the membrane. Z. bailii cultured with the drug myriocin, known to decrease cellular sphingolipid levels, exhibited significant growth inhibition in the presence of acetic acid, while growth in medium without acetic acid was unaffected by the myriocin addition. Furthermore, following an acetic acid pulse, the intracellular pH decreased more in myriocin‐treated cells than in control cells. This indicates a higher inflow rate of acetic acid and confirms that the reduction in growth of cells cultured with myriocin in the medium with acetic acid was due to an increase in membrane permeability, thereby demonstrating the importance of a high fraction of sphingolipids in the membrane of Z. bailii to facilitate acetic acid resistance; a property potentially transferable to desired production organisms suffering from weak acid stress. Biotechnol. Bioeng. 2016;113: 744–753. © 2015 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc.

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“…27. Many works have used various forms of US, 12,28–41 adaptive biasing force, 42,43 metadynamics, 44 and kinetic master equations. 45 Passive membrane permeability can also be calculated without the use of the solubility-diffusion equation via methods such as milestoning or directional milestoning.…”

Section: Introductionmentioning

confidence: 99%

Simulation-Based Approaches for Determining Membrane Permeability of Small Compounds

Lee

Comer

Herndon

et al. 2016

J. Chem. Inf. Model.

195

325

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Predicting the rate of nonfacilitated permeation of solutes across lipid bilayers is important to drug design, toxicology, and signaling. These rates can be estimated using molecular dynamics simulations combined with the inhomogeneous solubility-diffusion model, which requires calculation of the potential of mean force and position-dependent diffusivity of the solute along the transmembrane axis. In this paper, we assess the efficiency and accuracy of several methods for the calculation of the permeability of a model DMPC bilayer to urea, benzoic acid, and codeine. We compare umbrella sampling, replica exchange umbrella sampling, adaptive biasing forces, and multiple-walker adaptive biasing forces for the calculation of the transmembrane PMF. No definitive advantage for any of these methods in their ability to predict the permeability coefficient Pm was found, provided that a sufficiently long equilibration is performed. For diffusivities, a Bayesian inference method was compared to a Generalized Langevin method, both being sensitive to chosen parameters and the slow relaxation of membrane defects. Agreement within 1.5 log units of the computed Pm with experiment is found for all permeants and methods. Remaining discrepancies can likely be attributed to limitations of the force field as well as slowly relaxing collective movements within the lipid environment. Numerical calculations based on model profiles show that Pm can be reliably estimated from only a few data points, leading to recommendations for calculating Pm from simulations.

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Effects of Cholesterol on the Thermodynamics and Kinetics of Passive Transport of Water through Lipid Membranes

Cited by 45 publications

References 78 publications

Alpha-tocopherol inhibits pore formation in oxidized bilayers

Alpha-tocopherol inhibits pore formation in oxidized bilayers

Sphingolipids contribute to acetic acid resistance in Zygosaccharomyces bailii

Simulation-Based Approaches for Determining Membrane Permeability of Small Compounds

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