Molecular Dynamics Simulations of Ternary Membrane Mixture:  Phosphatidylcholine, Phosphatidic Acid, and Cholesterol

Cheng, Mary Hongying; Liu, Lu Tian; Saladino, Alexander C.; Xu, Yan; Tang, Pei

doi:10.1021/jp075467b

Cited by 29 publications

(46 citation statements)

References 53 publications

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“…Details of system preparations and MD simulations were provided in our previous publications 12, 13, 45. In short, the open- and closed-channel structures of the α4β2 nAChR were individually embedded in a pre-equilibrated ternary lipid bilayer51 and TIP3P water. Each system also contained sodium and chloride ions to neutralize the overall charge and to obtain a final ion concentration of 200 mM.…”

Section: Resultsmentioning

confidence: 99%

The role of structured water in mediating general anesthetic action on α4β2 nAChR

Willenbring

Tang

2010

Phys. Chem. Chem. Phys.

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Water is an essential component for many biological processes. Pauling proposed that water might play a critical role in general anesthesia by forming water clathrates around anesthetic molecules. To examine potential involvement of water in general anesthesia, we analyzed water within α4β2 nAChR, a putative protein target hypersensitive to volatile anesthetics. Experimental structurederived closed-and open-channel nAChR systems in a fully hydrated lipid bilayer were examined using all-atom molecular dynamics simulations. At the majority of binding sites in α4β2 nAChR, halothane replaced the slow-exchanging water molecules and caused a regional water population decrease. Only two binding sites had an increased quantity of water in the presence of halothane, where water arrangements resemble clathrate-like structures. The small number of such clathratelike water clusters suggests that the formation of water clathrates is unlikely to be a primary cause for anesthesia. Despite the decrease in water population at most of the halothane binding sites, the number of sites that can be occupied transiently by water is actually increased in the presence of halothane. Many of these water sites were located between two subunits or in regions containing agonist binding sites or critical structural elements for transducing agonist binding to channel gating. Changes in water sites in the presence of halothane affected water-mediated proteinprotein interactions and the protein dynamics, which can have direct impact on protein function. Collectively, water contributes to the action of anesthetics in proteins by mediating interactions between protein subunits and altering protein dynamics, instead of forming water clathrates around anesthetics.

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Section: Resultsmentioning

confidence: 99%

The role of structured water in mediating general anesthetic action on α4β2 nAChR

Willenbring

Tang

2010

Phys. Chem. Chem. Phys.

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“…The lipids 1-palmitoyl-2-oleoyl-sn-glycerol phosphatidic acid (POPA) and cholesterol (CHOL) were then added into the membrane such that the final ratio of POPC:POPA:CHOL was 3:1:1. This particular stoichiometry of the lipid molecules were chosen based on previous reports (Brannigan et al, 2008;Cheng et al, 2007;daCosta et al, 2002). The membrane was then further equilibrated to induce the appropriate disorder of a fluid-like bilayer.…”

Section: Generation and Simulation Of The Membrane-nachr Complexmentioning

confidence: 99%

Molecular mechanism of interactions of the physiological anti-hypertensive peptide catestatin with the neuronal nicotinic acetylcholine receptor

Sahu

Mohan

Sahu

et al. 2012

Journal of Cell Science

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SummaryCatestatin (CST), a chromogranin-A-derived peptide, is a potent endogenous inhibitor of the neuronal nicotinic acetylcholine receptor (nAChR). It exerts an anti-hypertensive effect by acting as a 'physiological brake' on transmitter release into the circulation. However, the mechanism of interaction of CST with nAChR is only partially understood. To unravel molecular interactions of the wild-type human CST (CST-WT) as well as its naturally occurring variants (CST-364S and CST-370L, which have GlyRSer and ProRLeu substitutions, respectively) with the human a3b4 nAChR, we generated a homology-modeled human a3b4 nAChR structure and solution structures of CST peptides. Docking and molecular dynamics simulations showed that ,90% of interacting residues were within 15 N-terminal residues of CST peptides. The rank order of binding affinity of these peptides with nAChR was: CST-370L.CST-WT.CST-364S; the extent of occlusion of the receptor pore by these peptides was also in the same order. In corroboration with computational predictions, circular dichroism analysis revealed significant differences in global structures of CST peptides (e.g. the order of a-helical content was: CST-370L.CST-WT.CST-364S). Consistently, CST peptides blocked various stages of nAChR signal transduction, such as nicotine-or acetylcholine-evoked inward current, rise in intracellular Ca 2+ and catecholamine secretion in or from neuron-differentiated PC12 cells, in the same rank order. Taken together, this study shows molecular interactions between human CST peptides and human a3b4 nAChR, and demonstrates that alterations in the CST secondary structure lead to the gain of potency for CST-370L and loss of potency for CST-364S. These findings have implications for understanding the nicotinic cholinergic signaling in humans.

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“…[17] However, the former cannot calculate an individual surface area of a lipid molecule, and in the latter, the accuracy of the calculated surface area depends on grid size. The Voronoi tessellation (VT) method is one of the more useful methods to calculate the area per lipid and has been applied to simple lipid bilayers, [18][19][20] mixed bilayers, [21][22][23] and bilayers with cholesterol [24,25] and other organic substrates. [26] Due to the large differences in size between protein and lipid molecules, the VT method cannot be applied directly to protein-membrane systems.…”

Section: Introductionmentioning

confidence: 99%

Analysis of lipid surface area in protein–membrane systems combining voronoi tessellation and monte carlo integration methods

2011

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All-atom molecular dynamics (MD) simulation has become a powerful research tool to investigate structural and dynamical properties of biological membranes and membrane proteins. The lipid structures of simple membrane systems in recent MD simulations are in good agreement with those obtained by experiments. However, for protein-membrane systems, the complexity of protein-lipid interactions makes investigation of lipid structure difficult. Although the area per lipid is one of the essential structural properties in membrane systems, the area in protein-membrane systems cannot be computed easily by conventional approaches like the Voronoi tessellation method. To overcome this limitation, we propose a new method combining the two-dimensional Voronoi tessellation and Monte Carlo integration methods. This approach computes individual surface areas of lipid molecules not only in bulk lipids but also in proximity to membrane proteins. We apply the method to all-atom MD trajectories of the sarcoplasmic reticulum Ca(2+)-pump and the SecY protein-conducting channel. The calculated lipid surface area is in agreement with experimental values and consistent with other structural parameters of lipid bilayers. We also observe changes in the average area per lipid induced by the conformational transition of the SecY channel. Our method is particularly useful for examining equilibration of lipids around membrane proteins and for analyzing the time course of protein-lipid interactions.

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Molecular Dynamics Simulations of Ternary Membrane Mixture: Phosphatidylcholine, Phosphatidic Acid, and Cholesterol

Cited by 29 publications

References 53 publications

The role of structured water in mediating general anesthetic action on α4β2 nAChR

The role of structured water in mediating general anesthetic action on α4β2 nAChR

Molecular mechanism of interactions of the physiological anti-hypertensive peptide catestatin with the neuronal nicotinic acetylcholine receptor

Analysis of lipid surface area in protein–membrane systems combining voronoi tessellation and monte carlo integration methods

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