Discreteness of Conductance Change in Bimolecular Lipid Membranes in the Presence of Certain Antibiotics

Hladky, Stephen B.; Haydon, D. A.

doi:10.1038/225451a0

Cited by 398 publications

(181 citation statements)

References 9 publications

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“…It contains 6.3 residues per turn, and the hydrogen bonding pattern between turns of the helix is the same as between chains of the parallel (3-pleated sheet conformation, hence the nomenclature (-helix. The spectroscopic data (UV, circular dichroism, and nuclear magnetic resonance) for gramicidin A in trifluoroethanol and dimethyl sulfoxide argue for a left-handed (3-helix (7,8), and the black lipid membrane studies are nicely consistent with the 33,3rhelix (1)(2)(3)5, and Hladky, S. B. & Haydon, D. A., personal communication) as being the conducting transmembrane channel.…”

supporting

confidence: 58%

A Molecular Theory of Ion-Conducting Channels: A Field-Dependent Transition Between Conducting and Nonconducting Conformations

Urry

1972

Proc. Natl. Acad. Sci. U.S.A.

135

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Structural and conformational requirements for an electric field-dependent transition between conducting and nonconducting macromolecular systems are: two kinetically interconvertible and energetically similar conformations, one conducting and the other nonconducting, which have axes spanning the lipid layer of biological membranes, but which have different net dipole -moments along those axes. Two examples are described. A previously defined helix, the TLD-helix now termed the #63,3-helix, is proposed as the conducting species, and the linear peptide correlate of the cyclic hexapeptide conformation containing two ,8-turns and an inversion element of symmetry is proposed as a nonconducting species. The latter is termed an anti-882-spiral and contains little or no net dipole moment per turn, whereas the j363,3-helix contains a net dipole moment along the helix axis of about 0.5 Debye per dipeptide unit. A related conducting and nonconducting pair with large net dipole moments of opposite sigp, termed s'yn-i36-spiral and j0%,4-helix, are also described. The spiral conformations are stabilized in a lipid layer by intermolecular hydrogen bonds, leading to a linear association of transmembrane structures. A conformational transition in one member of the array could lead to destabilization of an adjacent member of the array. The conformational analysis uses a concept of cyclic conformationswith linear conformational correlates.The anti-3862-spiral and #63,3-helix are derivable from the conformations of the cyclic structure L(L-Gly)3] , whereas the syn-132-spiral and 862,4-helix may be derived from the cyclic structure E(L-L-Gly)2 .The conformational analysis leads to the expectation that N-formyl-(L-Ala-L-Ala-Gly), would form conducting channels.If there should exist two kinetically interchangeable conformations that could span the lipid layer of biological membranes, but that would have substantially different net dipole moments oriented in transmembrane manner, then the application of an electric field across the membrane could lead to the interconversion from one species to the other. If one conformation is a conducting species, for example, a channel, and the other is nonconducting, then a field-dependent channel could form. It is the purpose of this manuscript to explicate two pairs of such conformations.A conducting transmembrane. channel has been described (refs 1-3 and Hladky, S. B. & Haydon, D. A., personal communication) that exhibits ion selectivity and a high specific conductance and for which a conformation has been proposed (4-6) and supported by spectroscopic data (6, 7). The proposed conformation is given in Fig. 1 for the ?6LD-helix of gramicidin A. As will be discussed in greater detail below, the term 6 3,s-helix is a more descriptive one. The fundamental requirement for this conformation is a specific aminoacid sequence. For gramicidin A, the requirement is an alternating (L-D),, optical isomeric sequence of hydrophobic amino acids with a glycine residue replacing one of the Dresidues. Acco...

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supporting

confidence: 58%

A Molecular Theory of Ion-Conducting Channels: A Field-Dependent Transition Between Conducting and Nonconducting Conformations

Urry

1972

Proc. Natl. Acad. Sci. U.S.A.

135

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“…The exact number and position of oxygen atoms is certainly not known, nor is the chemical nature of the oxygen-bearing groups, but there are reasons to suggest that one pair of oxygens is an ionized carboxylic acid. Some structure containing many other atoms is needed to support the important oxygen atoms, as for example in the cation-permeable, oxygen-lined pore formed by the polypeptide gramicidin A (Urry, 1971;Urry et al, 1971;Hladky and Haydon, 1970). The framework of supporting atoms would have some flexibility so that the static view in Fig.…”

Section: }5mentioning

confidence: 99%

The Permeability of the Sodium Channel to Organic Cations in Myelinated Nerve

Hille

1971

The Journal of General Physiology

628

320

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The relative permeability of sodium channels to 21 organic cations was studied in myelinated nerve fibers. Ionic currents under voltage-clamp conditions were measured in sodium-free solutions containing the test cation. The measured reversal potential and the Goldman equation were used to calculate relative permeabilities. The permeability sequence was: sodium ~ hydroxylamine > hydrazine > ammonium ~ formamidine ~ guanidine w hydroxyguanidine > aminoguanididine >> methylamine. The cations of the following compounds were not measurably permeant: N-methylhydroxylamine, methylhydrazine, methylamine, methylguanidine, acetamidine, dimethylamine, tetramethylammonium, tetraethylammonium, ethanolamine, choline, tris(hydroxymethyl)amino methane, imidazole, biguanide, and triaminoguanidine. Thus methyl and methylene groups render cations impermeant. The results can be explained on geometrical grounds by assuming that the sodium channel is an oxygen-lined pore about 3 A by 5 A in cross-section. One pair of oxygens is assumed to be an ionized carboxylic acid. Methyl and amino groups are wider than the 3 A width of the channel. Nevertheless, cations containing amino groups can slide through the channel by making hydrogen bonds to the oxygens. However, methyl groups, being unable to form hydrogen bonds, are too wide to pass through. This paper deals with the ionic selectivity of the excitability mechanism in nerve membranes. Previous work has shown that a variety of small organic cations can maintain the excitability of nerves in sodium-free solutions (Larramendi et al., 1956;Lorente de N6 et al

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“…The alternative mechanism is the formation of channels through the membrane, which provide pathways for ion transport. The hydrophobic, tryptophan-rich, linear gramicidin polypeptides were originally thought to function as ionophores [l-4], but recently emphasis has been directed to a possible channelforming role [ 5,6]. More specifically, have suggested that a head-to head association of two gramicidin molecules, each in a novel nL D helix conformation, provides a structure of the Correct dimensions to span a lipid bilayer and form a channel for the transfer of ions.…”

Section: Introductionmentioning

confidence: 99%