Molecular dynamics simulation of a bilayer of 200 lipids in the gel and in the liquid crystal phase

Heller, Helmut; Schaefer, Michael; Schulten, Klaus

doi:10.1021/j100133a034

Cited by 481 publications

(422 citation statements)

References 9 publications

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“…The crystal structure of C2A was rendered using MolScript (43) and Raster3D (44) according to a description file modified from Sutton et al (8). The simulated lipid bilayer was modified from Heller et al (45). The thickness of the hydrophilic (10 Å) and hydrophobic (15 Å) regions of one leaflet of the bilayer (32) are indicated in the model.…”

Section: Resultsmentioning

confidence: 99%

Membrane-embedded Synaptotagmin Penetrates cis ortrans Target Membranes and Clusters via a Novel Mechanism

Bai

Earles

Lewis

et al. 2000

Journal of Biological Chemistry

124

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The synaptic vesicle protein synaptotagmin I has been proposed to serve as a Ca 2؉ sensor for rapid exocytosis. Synaptotagmin spans the vesicle membrane once and possesses a cytoplasmic domain largely comprised of two C2 domains designated C2A and C2B. We have determined how deep the Ca 2؉ -binding loops of Ca 2؉ ⅐C2A penetrate into the lipid bilayer and report mutations in synaptotagmin that can uncouple membrane penetration from Ca 2؉ -triggered interactions with the SNARE complex. To determine whether C2A penetrates into the vesicle ("cis") or plasma ("trans") membrane, we reconstituted a fragment of synaptotagmin that includes the membrane-spanning and C2A domain (C2A-TMR) into proteoliposomes. Kinetics experiments revealed that cis interactions are rapid (<500 s). Binding in the trans mode was distinguished by the slow diffusion of trans target vesicles. Both modes of binding were observed, indicating that the linker between the membrane anchor and C2A domain functions as a flexible tether. C2A-TMR assembled into oligomers via a novel N-terminal oligomerization domain suggesting that synaptotagmin may form clusters on the surface of synaptic vesicles. This novel mode of clustering may allow for rapid Ca 2؉ -triggered oligomerization of the protein via the membrane distal C2B domain. Ca2ϩ -triggered fusion of synaptic vesicles with presynaptic plasma membrane mediates the release of neurotransmitters from neurons. The release process is extremely fast, occurring on the sub-millisecond time scale (1-3). Synaptotagmin I (hereafter referred to as synaptotagmin) is a Ca 2ϩ -binding synaptic vesicle protein that has been proposed to function as a Ca 2ϩ sensor that triggers release in response to Ca 2ϩ influx (4 -6). Structurally, synaptotagmin spans the vesicle membrane once and has a short intravesicular N-terminal domain and a large C-terminal cytoplasmic region that contains two C2 domains, designated C2A and C2B 1 (7). A charged "linker" segment connects the C2 domains to the transmembrane domain.The structure and biochemical properties of the C2A domain have been studied in detail. This domain forms a compact eight-stranded ␤-sandwich structure. Three flexible loops that protrude from one end of the domain mediate the binding of two to three Ca 2ϩ ions (8 -10). Recent fluorescence and NMR studies demonstrated that Ca 2ϩ -binding loops 1 and 3 penetrate into lipid bilayers in response to binding Ca 2ϩ (11)(12)(13). The second C2 domain (C2B) mediates the Ca 2ϩ -dependent oligomerization of synaptotagmin (14, 15), potentially clustering the cytoplasmic domain into a collar or ring-like structure that may regulate the opening or dilation of the fusion pore (16). Both C2 domains cooperate to mediate high affinity Ca 2ϩ -dependent binding of synaptotagmin to the plasma membrane proteins syntaxin (12,14) and 18). Syntaxin and SNAP-25 form a high affinity ternary complex with the synaptic vesicle protein synaptobrevin (19,20). This heterotrimer, designated the SNARE complex, has been proposed to function as the cor...

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Section: Resultsmentioning

confidence: 99%

Membrane-embedded Synaptotagmin Penetrates cis ortrans Target Membranes and Clusters via a Novel Mechanism

Bai

Earles

Lewis

et al. 2000

Journal of Biological Chemistry

124

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“…The membrane used to provide the lipid environment for the protein was constructed from a palmitoyloleoyl-phosphatidylcholine (POPC) membrane that consisted of an equilibrated rectangular bilayer with 100 POPC lipids in each leaflet. 21 Starting coordinates were obtained by expanding a previously equilibrated POPC bilayer to 274 lipids. Starting from the pure POPC bilayer, the human P-gp structure was inserted by using the VMD Membrane plug-in, 22 with the initial membrane position along the z axis determined by matching positions of headgroups with the Leu36, Thr37, Trp694, Arg695, Ile696, Leu697, Lys698, Leu699, Asn700, Ser701, Thr702 side chains of the P-gp transmembrane domain.…”

Section: Simulation Methodologymentioning

confidence: 99%

Multidrug resistance protein P-glycoprotein does not recognize nanoparticle C60: experiment and modeling

Xue

et al. 2012

Soft Matter

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Organisms have evolved stress-inducible defense responses such as the P-glycoprotein (P-gp)-mediated efflux system to maintain chemical homeostasis in cells for both endogenous and xenobiotic compounds. However, despite the extensive focus on the potential interactions of P-gp with small molecules, the effect of nanoparticles on this transporter is scarcely reported. Thus in this work, in vitro experiments combined with molecular dynamics (MD) simulations were carried out to investigate the interactions of the multidrug resistance (MDR) protein P-gp with fullerene (C 60 ), one of the most important nano-drug carriers. Upon exposure to fluorescence-labeled C 60 (0-70 mg mL À1 ) for 2 h, significant accumulation of C 60 is found in both the K562S and K562R cells, suggesting the incapability of P-gp to induce the efflux of this nanoparticle. In addition, in vitro inhibition assays also reveal that C 60 does not obviously hinder Pgp-mediated rhodamine-123 transport in both K562S and K562R cells. The theoretical simulations further reveal the mechanism involved in C 60 -P-gp interactions, i.e., the binding of C 60 barely induces the conformational changes of P-gp with RMSD of $4.8 A and radius of gyration of $41.5 A, and also no theoretical evidence shows that the C 60 acts as a substrate or inhibitor of P-glycoprotein. These results demonstrate the potential of C 60 as a good carrier candidate for MDR-targeted drug delivery, since organisms probably have not evolved to recognize this nanoparticle.

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“…The pore of the channel contained 50 water molecules, approximately 40 of them were located in the cavity. The channel protein was then inserted into a phosphatidylcholine ͑POPC͒ lipid bilayer 30,31 at a position where the C ␣ of Asp80 was located around the average position of the phosphate groups of the upper lipid layer. Because of the asymmetric shape of KcsA, the upper and lower parts of the bilayer contained different numbers of lipids, 45 and 59, respectively.…”

Section: A Molecular Modelmentioning

confidence: 99%

Cooperative transport in a potassium ion channel

Gwan

Baumgaertner

2007

The Journal of Chemical Physics

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Our current understanding of ion permeation through the selectivity filter of the KcsA potassium channel is based on the concept of a multi-ion transport mechanism. The details of this concerted movement, however, are not well understood. In the present paper we report on molecular dynamics simulations which provides new insights. It is shown that ion translocation is based on the collective hopping of ions and water molecules which is mediated by the flexible charged carbonyl groups lining the backbone of the pore. In particular, there is strong evidence for pairwise translocations where one ion and one water molecule form a bound state. We suggest a physical explanation of the observed phenomena employing a simple lattice model. It is argued that the water molecules can act as rectifiers during the hopping of ion-water pairs.

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Molecular dynamics simulation of a bilayer of 200 lipids in the gel and in the liquid crystal phase

Cited by 481 publications

References 9 publications

Membrane-embedded Synaptotagmin Penetrates cis ortrans Target Membranes and Clusters via a Novel Mechanism

Membrane-embedded Synaptotagmin Penetrates cis ortrans Target Membranes and Clusters via a Novel Mechanism

Multidrug resistance protein P-glycoprotein does not recognize nanoparticle C60: experiment and modeling

Cooperative transport in a potassium ion channel

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