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Andersen, Olaf S.; Apell, Hans-Jürgen; Bamberg, Ernst; Busath, David D.; Koeppe, Roger E.; Sigworth, Fred J.; Szabó, Gábor; Urry, Dan W.; Woolley, G. Andrew

doi:10.1038/10648

Cited by 90 publications

(30 citation statements)

References 12 publications

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“…Generally, it is known that there are two general classes of folding patterns for gA, resulting in two different types of conformations. One conformational class is the (right-handed) head-to-head, SS β 6.3 -helix, which functions as a cation-conducting channel (45, 46). The other conformational class is a family of DS intertwined double helices (47-50).…”

Section: Discussionmentioning

confidence: 99%

The Membrane Interface Dictates Different Anchor Roles for “Inner Pair” and “Outer Pair” Tryptophan Indole Rings in Gramicidin A Channels

Lum

Kim

et al. 2011

Biochemistry

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We investigated the effects of substituting two of the four tryptophans (the “inner pair” Trp9,11 or the “outer pair” Trp13,15) in gramicidin A (gA) channels. The conformational preferences of the double-substituted gA analogues were assessed using circular dichroism spectroscopy and size-exclusion chromatography, which show that the inner tryptophans 9 and 11 are critical for the gA’s conformational preference in lipid bilayer membranes. [Phe13,15]gA largely retains the single-stranded helical channel structure, whereas of [Phe9,11]gA exists primarily as double-stranded conformers. Within this context, the 2H-NMR spectra from labeled tryptophans were used to examine the changes in average indole ring orientations, induced by the Phe substitutions and by the shift in conformational preference. Using a method for deuterium labeling of already synthesized gAs, we introduced deuterium selectively onto positions C2 and C5 of the remaining tryptophan indole rings in the substituted gA analogues for solid-state 2H-NMR spectroscopy. The (least possible) changes in orientation and overall motion of each indole ring were estimated from the experimental spectra. Regardless of the mixture of backbone folds, the indole ring orientations observed in the analogues are similar to those found previously for gA channels. Both Phe-substituted analogues form single-stranded channels, as judged from the formation of heterodimeric channels with the native gA. [Phe13,15]gA channels have Na+ currents that are ~50% and lifetimes ~80% those of native gA channels. The double-stranded conformer(s) of [Phe9,11]gA do not form detectable channels. The minor single-stranded population of [Phe9,11]gA forms channels with Na+ currents that are ~25% and single-channel lifetimes that are ~300% those of native gA channels. Our results suggest that Trp9 and Trp11, when “reaching” for the interface, tend to drive both monomer folding (to “open” a channel) and dimer dissociation (to “close” a channel). Furthermore, the dipoles of Trp9 and Trp11 are relatively more important for the single-channel conductance than are the dipoles of Trp13 and Trp15.

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Section: Discussionmentioning

confidence: 99%

The Membrane Interface Dictates Different Anchor Roles for “Inner Pair” and “Outer Pair” Tryptophan Indole Rings in Gramicidin A Channels

Lum

Kim

et al. 2011

Biochemistry

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“…Recently, however, with the appearance of a new double-stranded (DS) intertwined structure, this consensus has been challenged (16), and there appears to be a controversy as to whether the ion-conducting form is a SS or DS structure (17)(18)(19)(20). To clarify this issue further, we present calculations of the stability of gramicidin in both SS and DS structures in model lipid bilayers.…”

mentioning

confidence: 96%

Stability of an Ion Channel in Lipid Bilayers: Implicit Solvent Model Calculations with Gramicidin

et al. 2002

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Gramicidin is a helical peptide, 15 residues in length, which dimerizes to form ion-conducting channels in lipid bilayers. Here we report calculations of its free energy of transfer from the aqueous phase into bilayers of different widths. The electrostatic and nonpolar contributions to the desolvation free energy were calculated using implicit solvent models, in which gramicidin was described in atomic detail and the hydrocarbon region of the membrane was described as a slab of hydrophobic medium embedded in water. The free energy penalties from the lipid perturbation and membrane deformation effects, and the entropy loss associated with gramicidin immobilization in the bilayer, were estimated from a statistical thermodynamic model of the bilayer. The calculations were carried out using two classes of experimentally observed conformations: a head-to-head dimer of two single-stranded (SS) beta-helices and a double-stranded (DS) intertwined double helix. The calculations showed that gramicidin is likely to partition into the bilayer in all of these conformations. However, the SS conformation was found to be significantly more stable than the DS in the bilayer, in agreement with most of the experimental data. We tested numerous transmembrane and surface orientations of gramicidin in bilayers of various widths. Our calculations indicate that the most favorable orientation is transmembrane, which is indeed to be expected from a channel-forming peptide. The calculations demonstrate that gramicidin insertion into the membrane is likely to involve a significant deformation of the bilayer to match the hydrophobic width of the peptide (22 A), again in good agreement with experimental data. Interestingly, deformation of the bilayer was induced by all of the gramicidin conformations.

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“…To conserve the head-to-head conformation of gA dimers [14] in the shorter peptides, we have linked the monomers by a succinyl group [ Fig. 1(a)].…”

mentioning

confidence: 99%

Mobility of a One-Dimensional Confined File of Water Molecules as a Function of File Length

et al. 2006

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Confinement of water by pore geometry to a one-dimensional file of molecules interacting with the pore alters the diffusion coefficient D(W). Here we report an exponential dependence of D(W) on the number of water positions in the pore. The result is based on measurements of single channel water permeabilities of structurally similar peptidic nanopores of different length. The inconsistency with predictions from continuum or kinetic models indicates that pore occupancy is reduced in single file transport. In longer pores (e.g., in aquaporins) the presence of charged residues increases D(W).

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Cited by 90 publications

References 12 publications

The Membrane Interface Dictates Different Anchor Roles for “Inner Pair” and “Outer Pair” Tryptophan Indole Rings in Gramicidin A Channels

The Membrane Interface Dictates Different Anchor Roles for “Inner Pair” and “Outer Pair” Tryptophan Indole Rings in Gramicidin A Channels

Stability of an Ion Channel in Lipid Bilayers: Implicit Solvent Model Calculations with Gramicidin

Mobility of a One-Dimensional Confined File of Water Molecules as a Function of File Length

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