Gramicidines structure

A. Side view of channel spanning the lipid layer of a planar lipid bilayer, The structure is comprised of two monomers, each in a left-handed, single stranded p -helical conformation, and joined together at the head or formyl end by means of six, intermolecular hydrogen bonds. The two formyl protons are seen at the center of the structure in this view. Replacement of these protons by methyls destabilizes the conducting dimer as shown with N-acetyl desformyl Gramicidin A (Fig. 3D). 

Urry, D. W. On the Molecular Structure and Ion Transport Mechanism of the Gramicidin Transmembrane Channel. In Membranes and Transport, Vol. 2, (ed. Martonosi, A.), p. 285, Plenum Publishing Corporation, New York 1982... 

A good understanding of the properties of water is thus essential as we move to more complicated systems. We have been involving in the study of aqueous solution of many important biological molecules, such as acetylcholine, Gramicidin, deoxydinucleoside phosphate and proflavin, and DNA, etc., first at the Monte Carlo level and slowly moving to the molecular dynamics simulations. We will discuss some of the new results on the hydration structure and the dynamics of B- and Z-DNA in the presence of counterions in the following. 

Naturally occurring gramicidin is a mixture of at least six linear pentadecapeptide antibiotics of closely related structure produced by Bacillus brevis 207). The amino acid sequence of the major component [Valjgramicidin A was reported by Sarges and Witkop208 in 1965 ... 

X-ray diffraction studies on gramicidin commenced as early as 1949 218-219> and this early work pointed to a helical structure 220). Recent work by Koeppe et al. 221) on gramicidin A crystallised from methanol (/%) and ethanol (.P212121) has shown that the helical channel has a diameter of about 5 A and a length of about 32 A in both cases. The inclusion complexes of gramicidin A with CsSCN and KSCN (P212121) have channels that are wider (6-8 A) and shorter (26 A) than the uncomplexed dimer 221 222). Furthermore there are two cation binding sites per channel situated either 2.5 A from either end of the channel or 2.5 A on each side of its centre 222) Unfortunately these data do not permit a choice to be made from the helical models (i)—(iv) and it is not certain if the helical canals studied are the same as those involved in membrane ion transport. 

Major effort has therefore been applied to study of the helical channels by non-erystallographic methods in order to discriminate unambigously between the likely models. This has resulted in the gramicidin ion channel not only being the first clearly identified example but also the most characterised in structural terms. The bulk of... 

Fig. 24. Proposed structure of the Gramicidin A dimer showing the intramolecular and intermolecular hydrogen bonding arrangement. Numbers refer to the amino acid residues Peptide side groups are omitted for clarity.

Fig. 25. Top view of a space-filling model of the proposed Gramicidin A dimer structure, showing the transmembrane channel. [Photograph courtesy of D. A. Haydon]...

It should be noted that in forming this dimeric channel structure all the hydrogen bonds are parallel to the channel axis and that the inner surface is lined with the polar polypeptide groups. In addition the various lipophilic side chains coat the outer wall of the structure and are thus in contact with the lipid hydrocarbon chains. The resulting gramicidin A channel is a most efficient means of ion transport with approximately 107 sodium ions traversing the channel per second, under conditions of 1 M NaCl, 100 mV applied potential and a temperature of 25 °C 225). The detailed mechanism by which this can be achieved is under active study 226). 

The third current approach is synthesis of peptide chains as models for the helical peptaibol (Section 8.2) and gramicidin (Section 8.3) ion channels. Considerable work has been carried out in the former area, involving synthesis of Aib-containing small peptides, in order to obtain conformational data applicable to the more complex oligopeptide antibiotics. By working with such fragments it has been possible to obtain valuable X-ray crystal structure information on the helical conformation of ala-methin 246), emerimicin 247), suzukacillin 248), and other members of the peptaibol series. 

Salgado J, Grage SL, Kondejewski LH, Hodges RS, McElhaney RN, Ulrich AS (2001) Membrane-bound structure and alignment of the antimicrobial beta-sheet peptide gramicidin S derived from angular and distance constraints by solid state F-19-NMR. J Biomol NMR 21 191-208... 

Afonin S, Durr UHN, Wadhwani P, Salgado J, Ulrich AS (2008) Solid state NMR structure analysis of the antimicrobial peptide gramicidin S in lipid membranes concentration-depen-dent re-alignment and self-assembly as a beta-barrel. Top Curr Chem 273 139-154... 

Kondejewski LH, Farmer SW, Wishart DS, Kay CM, Hancock REW, Hodges RS (1996) Modulation of structure and antibacterial and hemolytic activity by ring size in cyclic gramicidin S analogs. J Biol Chem 271 25261-25268... 

Other workers began to study the structure of gramicidin. Christensen and coworkers12 isolated crystalline tryptophane and leucine from a hydrolysate. They found no evidence for a fatty acid component and established that phenylalanine, proline and hydroxyproline were absent from a hydrolysate. These workers isolated alanine diox-pyridate from a hydrolysate and also established that gramicidin contained a compound with vicinal hydroxy and amino groups. They speculated that this compound might be serine or isoserine and proposed that gramicidin contains two tryptophane, 2 leucine, 2 or 3 alanine and 1 hydroxyamino residues or a multiple of this composition. 

There was some evidence that the preparations of gramicidin used in this structural work were not completely... 

In a review paper, Dr. Synge recapitulated the early structural work on gramicidin and indicated that x-ray diffraction was incapable of distinguishing a gramicidin fraction purified by counter current analysis from the heterogeneous starting material. 

A provisional structure for gramicidin was proposed by Gavrilov and Akimova30. 

Urry and coworkers 4 O 1 1 proposed a left-handed helical structure for gramicidin A. This conformation can undergo ion induced relaxations which provides a mechanism for the movement of the ion along the channel. These workers confirmed this proposed structure by nuclear magnetic resonance spectrometry1 2. 

As discussed in Section 2, the chemical structure of the various fractions has now been elucidated. The general formula for gramicidin is shown below, where R and R are different amino acid residues depending on the particular type of gramicidin. 

As was mentioned in Section 2, x-ray diffraction was used in an effort to establish the structure of the gramicidin complex25 29 29. These studies were frustrated by the fact that the gramicidin was not chemically pure but was a mixture of components. 

The conformation of gramicidin in aqueous solution has been extensively studied. A lipophilic left-handed helical structure has been proposed for gramicidin A 0 1 1. it was proposed that the mode of action of gramicidin is due to the formation of ion transport channels across biological membranes. 

The first structures of this kind were reported in 1993 pectate lyase G from Erwinia chrysanthemi (Yoder et al, 1993) and alkaline protease from Pseudomonas aeruginosa (Baumann et al, 1993). Based on consideration of these crystal structures, the term parallel //-helix was introduced for a fold containing three //-strands per coil, and parallel //-roll for a fold with two //-strands per coil (Baumann etal, 1993 Yoder andjurnak, 1995 Yoder et al., 1993). The epithet parallel was intended to emphasize the distinction between these folds and the previously observed helical structure of the antibiotic gramicidin which contains both l- and D-amino acids and... 

Langs, D. A. (1988). Three-dimensional structure at 0.86 A of the uncomplexed form of the transmembrane ion channel peptide gramicidin A. Science 241, 188-191. 

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