Structural Dynamics of the S4 Voltage-Sensor Helix in Lipid Bilayers Lacking Phosphate Groups

Andersson, Magnus; Freites, J. Alfredo; Tobias, Douglas J.; White, Stephen H.

doi:10.1021/jp2001964

Cited by 17 publications

(21 citation statements)

References 53 publications

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“…Strong H-bonding interactions with the lipid’s phosphate moiety have profound implications on the molecular organization of membrane-active compounds. For example, it has been shown that a lipid’s phosphate moiety plays important roles in orchestrating membrane insertion of arginine monomers 48 , anchoring of the antimicrobial peptide protegrin-1 49 , and regulating the voltage-gated potassium channel 50 . In ether bilayers, the prevalent association of OH-Chol with the phosphate oxygen also reduces the hydration level near the phosphate, as the interfacial water molecules that normally associate with the phosphate oxygen are displaced by the OH-Chol.…”

Section: Discussionmentioning

confidence: 99%

Interactions between Ether Phospholipids and Cholesterol As Determined by Scattering and Molecular Dynamics Simulations

et al. 2012

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Cholesterol and ether lipids are ubiquitous in mammalian cell membranes, and their interactions are crucial in ether lipid mediated cholesterol trafficking. We report on cholesterol’s molecular interactions with ether lipids as determined using a combination of small-angle neutron and X-ray scattering, and all-atom molecular dynamics (MD) simulations. A scattering density profile model for an ether lipid bilayer was developed using MD simulations, which was then used to simultaneously fit the different experimental scattering data. From the analysis of the data the various bilayer structural parameters were obtained. Surface area constrained MD simulations were also performed to reproduce the experimental data. This iterative analysis approach resulted in good agreement between the experimental and simulated form factors. The molecular interactions taking place between cholesterol and ether lipids were then determined from the validated MD simulations. We found that in ether membranes, cholesterol primarily hydrogen bonds with the lipid headgroup phosphate oxygen, while in their ester membrane counterparts, cholesterol hydrogen bonds with the backbone ester carbonyls. This different mode of interaction between ether lipids and cholesterol induces cholesterol to reside closer to the bilayer surface, dehydrating the headgroup’s phosphate moiety. Moreover, the three-dimensional lipid chain spatial density distribution around cholesterol indicates anisotropic chain packing, causing cholesterol to tilt. These insights lend a better understanding of ether lipid mediated cholesterol trafficking and the roles that the different lipid species have in determining the structural and dynamical properties of membrane associated biomolecules.

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Section: Discussionmentioning

confidence: 99%

Interactions between Ether Phospholipids and Cholesterol As Determined by Scattering and Molecular Dynamics Simulations

et al. 2012

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“…In addition to POPA and CHOL, positively charged lipid DOTAP has been shown to inhibit KvAP gating (7,8,11). MD simulations reveal that DOTAP lipids move away from the S4 helix because of the repulsive interactions between the positive charges on the DOTAP and the S4 segment (47). Furthermore, higher water penetration was observed in the S4 vicinity (47).…”

Section: Electromechanical Model Predicts Dotap-mediated Inhibition Omentioning

confidence: 99%

“…MD simulations reveal that DOTAP lipids move away from the S4 helix because of the repulsive interactions between the positive charges on the DOTAP and the S4 segment (47). Furthermore, higher water penetration was observed in the S4 vicinity (47). We employed our electromechanical continuum model to quantify the consequences of these findings on channel gating.…”

Section: Electromechanical Model Predicts Dotap-mediated Inhibition Omentioning

confidence: 99%

Electromechanics of lipid-modulated gating of Kv channels

Thomas

Mandadapu

Agrawal

2020

Preprint

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Experimental studies reveal that anionic lipid POPA and nonphospholipid cholesterol inhibit the gating of voltage-sensitive potassium (Kv) channels at 5 − 10% molar concentrations. Intriguingly, other anionic lipids similar to POPA, like POPG, have minimal impact on the gating of the same channels for reasons that remain obscure. Our long-timescale atomistic simulations show that POPA preferentially solvates the voltage sensor domains of Kv channels by direct electrostatic interactions between the positively charged arginine and negatively charged phosphate groups. Cholesterol solvates the voltage sensor domains through CH-π interactions between the cholesterol rings and the aromatic side chains of phenylalanine and tyrosine residues. A continuum electromechanical model predicts that POPA lipids may restrict the vertical motion of voltage-sensor domain through direct electrostatic interactions, while cholesterol may oppose the radial motion of the pore domain of the channel by increasing the mechanical rigidity of the membrane. The electromechanical model predictions are consistent with measurements of the activation curves of Kv channels for various lipids. The atomistic simulations also suggest that the solvation due to POPG is much weaker likely due to its bigger headgroup size. Thus the channel activity appears to be tied to the local lipid environment, allowing lipids to regulate channel gating in low concentrations.

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“…The issue of convergence has been rectified in part by running several long simulations and using non-equilibrium sampling method or steered MD to calculate the observables of interest. A series of extended simulations (~100 ns) on the voltage sensor domain of potassium channels revealed the importance of lipid phosphates in accommodating the significantly charged S4 helix [22]. Using umbrella sampling, potential of mean force has been calculated for permeation and effect of a potassium ion on the second ion passing through gramicidin A channel [23].…”

Section: Bioinformatics -Updated Features and Applications 86mentioning

confidence: 99%

Bioinformatics for Membrane Lipid Simulations: Models, Computational Methods, and Web Server Tools

Leong¹,

Lim²,

Choong³

2016

Bioinformatics - Updated Features and Applications

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Biological membranes are complex environments consisting of different types of lipids and membrane proteins. The structure of a lipid bilayer is typically difficult to study because the membrane liquid crystalline state is made up of multiple disordered lipid molecules. This complicates the description of the lipid membrane properties by the conformation of any single lipid molecule. Molecular dynamics (MD) simulations have been used extensively to investigate properties of membrane lipids, lipid vesicles, and membrane protein systems. All-atom membrane models can elucidate detailed contacts between membrane proteins and its surrounding lipids, while united-atom and coarsegrained description have allowed larger models and longer timescales up to microsecond mark to be probed. Additionally, membrane models with mixed phospholipids and lipopolysaccharide content have made it possible to model improved views of biological membranes. Here, we present an overview of commonly used lipid force fields by the biosimulation community, useful tools for membrane MD simulations, and recent advances in membrane simulations.

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Structural Dynamics of the S4 Voltage-Sensor Helix in Lipid Bilayers Lacking Phosphate Groups

Cited by 17 publications

References 53 publications

Interactions between Ether Phospholipids and Cholesterol As Determined by Scattering and Molecular Dynamics Simulations

Interactions between Ether Phospholipids and Cholesterol As Determined by Scattering and Molecular Dynamics Simulations

Electromechanics of lipid-modulated gating of Kv channels

Bioinformatics for Membrane Lipid Simulations: Models, Computational Methods, and Web Server Tools

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