g_membed: Efficient insertion of a membrane protein into an equilibrated lipid bilayer with minimal perturbation

Wolf, Maarten G.; Hoefling, Martin; Aponte-Santamaría, Camilo; Grubmüller, Helmut; Groenhof, Gerrit

doi:10.1002/jcc.21507

Cited by 374 publications

(326 citation statements)

References 28 publications

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“…The membrane system was built by the g_membed 40 tool in Gromacs 41 V4.6.3 with the receptor crystal structure pre-aligned in the Orientations of Proteins in Membranes (OPM) database 42,43 . Pre-equilibrated 132 POPC lipids coupled with 9,200 TIP3P water molecules in a box B70 Å Â 70 Å Â 98 Å were used for building the protein/membrane system.…”

Section: Methodsmentioning

confidence: 99%

Activation of G-protein-coupled receptors correlates with the formation of a continuous internal water pathway

et al. 2014

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Recent crystal structures of G-protein-coupled receptors (GPCRs) have revealed ordered internal water molecules, raising questions about the functional role of those waters for receptor activation that could not be answered by the static structures. Here, we used molecular dynamics simulations to monitor-at atomic and high temporal resolutionconformational changes of central importance for the activation of three prototypical GPCRs with known crystal structures: the adenosine A 2A receptor, the b 2 -adrenergic receptor and rhodopsin. Our simulations reveal that a hydrophobic layer of amino acid residues next to the characteristic NPxxY motif forms a gate that opens to form a continuous water channel only upon receptor activation. The highly conserved tyrosine residue Y 7.53 undergoes transitions between three distinct conformations representative of inactive, G-protein activated and GPCR metastates. Additional analysis of the available GPCR crystal structures reveals general principles governing the functional roles of internal waters in GPCRs.

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Section: Methodsmentioning

confidence: 99%

Activation of G-protein-coupled receptors correlates with the formation of a continuous internal water pathway

et al. 2014

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“…H537, the Switch motif, was set protonated for the ATP‐bound simulations, and neutral for the ADP‐bound ones. The protein in complex with either ATP or ADP was embedded in a 1‐palmitoyl‐2‐oleoyl‐sn‐glycero‐3‐phosphocholine (POPC) bilayer using g_membed (Wolf et al , 2010), with a total of 500 lipids. The simulation box, including water and ions to neutralize the system, was 13 × 13 × 16 nm.…”

Section: Methodsmentioning

confidence: 99%

Structural basis for antibacterial peptide self‐immunity by the bacterial ABC transporter McjD

et al. 2017

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Certain pathogenic bacteria produce and release toxic peptides to ensure either nutrient availability or evasion from the immune system. These peptides are also toxic to the producing bacteria that utilize dedicated ABC transporters to provide self‐immunity. The ABC transporter McjD exports the antibacterial peptide MccJ25 in Escherichia coli. Our previously determined McjD structure provided some mechanistic insights into antibacterial peptide efflux. In this study, we have determined its structure in a novel conformation, apo inward‐occluded and a new nucleotide‐bound state, high‐energy outward‐occluded intermediate state, with a defined ligand binding cavity. Predictive cysteine cross‐linking in E. coli membranes and PELDOR measurements along the transport cycle indicate that McjD does not undergo major conformational changes as previously proposed for multi‐drug ABC exporters. Combined with transport assays and molecular dynamics simulations, we propose a novel mechanism for toxic peptide ABC exporters that only requires the transient opening of the cavity for release of the peptide. We propose that shielding of the cavity ensures that the transporter is available to export the newly synthesized peptides, preventing toxic‐level build‐up.

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“…The model by Choudhary et al (2007) incorporates a larger fraction of the sequence of the pore to which conotoxin GIIIA was docked. This channel model was embedded in the octane phase of a water-octane biphasic cell, which was used to mimic a bilayer with the GROMACS program g_membed (Wolf et al, 2010). This system contained 19,499 water molecules and 575 octane molecules, enclosed in a 83 ϫ 88 ϫ 110-Å box using a single sodium ion to balance the overall charge of the system.…”

Section: Methodsmentioning

confidence: 99%

Orientation of μ-Conotoxin PIIIA in a Sodium Channel Vestibule, Based on Voltage Dependence of Its Binding

McArthur¹,

Singh²,

O’Mara³

et al. 2011

Mol Pharmacol

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Mutant cycle analysis has been used in previous studies to constrain possible docking orientations for various toxins. As an independent test of the bound orientation of -conotoxin PIIIA, a selectively targeted sodium channel pore blocker, we determined the contributions to binding voltage dependence of specific residues on the surface of the toxin. A change in the "apparent valence" (z␦) of the block, which is associated with a change of a specific toxin charge, reflects a change in the charge movement within the transmembrane electric field as the toxin binds. Toxin derivatives with charge-conserving mutations (R12K, R14K, and K17R) showed z␦ values similar to those of wild type (0.61 Ϯ 0.01, mean Ϯ S.E.M.). Chargechanging mutations produced a range of responses. Neutralizing substitutions for Arg14 and Lys17 showed the largest reductions in z␦ values, to 0.18 Ϯ 0.06 and 0.20 Ϯ 0.06, respectively, whereas unit charge-changing substitutions for Arg12, Ser13, and Arg20 gave intermediate values (0.24 Ϯ 0.07, 0.33 Ϯ 0.04, and 0.32 Ϯ 0.05), which suggests that each of these residues contributes to the dependence of binding on the transmembrane voltage. Two mutations, R2A and G6K, yielded no significant change in z␦. These observations suggest that the toxin binds with Arg2 and Gly6 facing the extracellular solution, and Arg14 and Lys17 positioned most deeply in the pore. In this study, we used molecular dynamics to simulate toxin docking and performed Poisson-Boltzmann calculations to estimate the changes in local electrostatic potential when individual charges were substituted on the toxin's surface. Consideration of two limiting possibilities suggests that most of the charge movement associated with toxin binding reflects sodium redistribution within the narrow part of the pore.

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g_membed: Efficient insertion of a membrane protein into an equilibrated lipid bilayer with minimal perturbation

Cited by 374 publications

References 28 publications

Activation of G-protein-coupled receptors correlates with the formation of a continuous internal water pathway

Activation of G-protein-coupled receptors correlates with the formation of a continuous internal water pathway

Structural basis for antibacterial peptide self‐immunity by the bacterial ABC transporter McjD

Orientation of μ-Conotoxin PIIIA in a Sodium Channel Vestibule, Based on Voltage Dependence of Its Binding

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