Structure of Dipalmitoylphosphatidylcholine/Cholesterol Bilayer at Low and High Cholesterol Concentrations: Molecular Dynamics Simulation

Smondyrev, Alexander M.; Berkowitz, Max L.

doi:10.1016/s0006-3495(99)77049-9

Cited by 280 publications

(277 citation statements)

References 44 publications

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“…The configuration of cholesterol displayed in Figure 7 is typical, with the steroid body inserted radially into the micelle and the hydroxyl group in the interfacial region hydrogen bonded with a phospholipid carbonyl oxygen. The packing of cholesterol is similar to its packing within phospholipid bilayers, as assessed by a number of recent MD simulations (e.g., refs [35][36][37][38]. Although mostly solvated as individual molecules, cholesterol molecules appear to form pairs as well, around 35% of the time.…”

Section: Aggregationmentioning

confidence: 66%

Molecular Dynamics Simulations of Mixed Micelles Modeling Human Bile

Marrink

Mark

2002

Biochemistry

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Extensive molecular dynamics (MD) simulations of binary systems of phospholipids and bile salts, a model for human bile, have been performed. Recent progress in hardware and software development allows simulation of the spontaneous aggregation of the constituents into small mixed micelles, in agreement with experimental observations. The MD simulations reveal the structure of these micelles at atomic detail. The phospholipids are packed radially with their headgroups at the surface and the hydrophobic tails pointing toward the micellar center. The bile salts act as wedges between the phospholipid headgroups, with their hydrophilic sides exposed to the aqueous environment. The structure of the micelles strongly resembles the previously proposed radial shell model. Simulations including small fractions of cholesterol reveal how cholesterol is solubilized inside these mixed micelles without changing their overall structure.

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Section: Aggregationmentioning

confidence: 66%

Molecular Dynamics Simulations of Mixed Micelles Modeling Human Bile

Marrink

Mark

2002

Biochemistry

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“…If one subtracts from the total PMF (Fig. 3, black curve) all contributions from charged and polar moieties within the core, one is left with the Born dehydration (from interactions with bulk electrolyte and lipid hydrocarbon, estimated to be 15-25 kcal/mol) plus interactions with the membrane interfaces [14-19 kcal/mol, assuming dipolar potentials of 600-800 mV (30,31)]. The fact that the barrier in the overall PMF is 17 kcal/mol is a result of lipid and water PMF contributions being insufficient to overcome this substantial (ϳ35 kcal/mol) electrostatic barrier presented by the membrane.…”

Section: Resultsmentioning

confidence: 99%

On the thermodynamic stability of a charged arginine side chain in a transmembrane helix

Dorairaj

Allen²

2007

Proc. Natl. Acad. Sci. U.S.A.

249

397

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Biological membranes consist of bilayer arrangements of lipids forming a hydrophobic core that presents a physical barrier to all polar and charged molecules. This long-held notion has recently been challenged by biological translocon-based experiments that report small apparent free energies to insert charged side chains near the center of a transmembrane (TM) helix. We have carried out fully atomistic simulations to provide the free-energy profile for moving a TM helix containing a protonated Arg side chain across a lipid bilayer. Our results reveal the fundamental thermodynamics governing the stability of charged side chains in membranes and the microscopic interactions involved. Despite local membrane deformations, where large amounts of water and lipid head groups are pulled into the bilayer to interact with Arg, the free-energy barrier is 17 kcal/mol. We provide a rationale for the differences in our microscopic free energies and cell biological experiments using free-energy calculations that indicate that a protonated Arg at the central residue of a TM helix of the Leader peptidase might reside close to the interface and not at the membrane center. Our findings have implications for the gating mechanisms of voltage-gated ion channels, suggesting that movements of protonated Arg residues through the membrane will be prohibited.

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“…Analogously to simple model bilayers, acyl chain ordering in biological membranes has been extrapolated to effect an increase in membrane thickness. According to data obtained from model phospholipid͞cholesterol bilayers, molar cholesterol to phospholipid ratios of 0.12 and 1 should lead to increases in bilayer thickness of 2 and 7 Å, respectively, compared with systems with no cholesterol (18)(19)(20). Thus, the predicted decrease in bilayer thickness on cholesterol depletion would have been Ϸ2 Å (instead of Յ1 Å) for ER and Golgi membranes and Ϸ5 Å (instead of Յ1 Å) for basolateral and apical plasma membranes, given cholesterol-tophospholipid molar ratios of 0.08-0.1, 0.16-0.2, and 0.4-0.76, respectively (22,(48)(49)(50)(51).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, cholesterol has also been shown to affect the thickness of artificial bilayer systems in vitro. Extensive experimental and computational data for pure phospholipid͞cholesterol systems have demonstrated that, under certain circumstances, cholesterol increases bilayer thickness (18)(19)(20), presumably due to the ordering of the acyl chains of phospholipids. Because cholesterol is ubiquitous in eukaryotic cell membranes, it has been suggested that cholesterol is a principal modulator of bilayer thickness in these cells.…”

mentioning

confidence: 99%

Modulation of the bilayer thickness of exocytic pathway membranes by membrane proteins rather than cholesterol

Mitra

Ubarretxena-Belandia

Taguchi

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

412

307

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A biological membrane is conceptualized as a system in which membrane proteins are naturally matched to the equilibrium thickness of the lipid bilayer. Cholesterol, in addition to lipid composition, has been suggested to be a major regulator of bilayer thickness in vivo because measurements in vitro have shown that cholesterol can increase the thickness of simple phospholipid͞cholesterol bilayers. Using solution x-ray scattering, we have directly measured the average bilayer thickness of exocytic pathway membranes, which contain increasing amounts of cholesterol. The bilayer thickness of membranes of the endoplasmic reticulum, the Golgi, and the basolateral and apical plasma membranes, purified from rat hepatocytes, were determined to be 37.5 ؎ 0.4 Å, 39.5 ؎ 0.4 Å, 35.6 ؎ 0.6 Å, and 42.5 ؎ 0.3 Å, respectively. After cholesterol depletion using cyclodextrins, Golgi and apical plasma membranes retained their respective bilayer thicknesses whereas the bilayer thickness of the endoplasmic reticulum and the basolateral plasma membrane decreased by 1.0 Å. Because cholesterol was shown to have a marginal effect on the thickness of these membranes, we measured whether membrane proteins could modulate thickness. Protein-depleted membranes demonstrated changes in thickness of up to 5 Å, suggesting that (i) membrane proteins rather than cholesterol modulate the average bilayer thickness of eukaryotic cell membranes, and (ii) proteins and lipids are not naturally hydrophobically matched in some biological membranes. A marked effect of membrane proteins on the thickness of Escherichia coli cytoplasmic membranes, which do not contain cholesterol, was also observed, emphasizing the generality of our findings.

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Structure of Dipalmitoylphosphatidylcholine/Cholesterol Bilayer at Low and High Cholesterol Concentrations: Molecular Dynamics Simulation

Cited by 280 publications

References 44 publications

Molecular Dynamics Simulations of Mixed Micelles Modeling Human Bile

Molecular Dynamics Simulations of Mixed Micelles Modeling Human Bile

On the thermodynamic stability of a charged arginine side chain in a transmembrane helix

Modulation of the bilayer thickness of exocytic pathway membranes by membrane proteins rather than cholesterol

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