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Top Curr Chem. 2008;273:139-54. doi: 10.1007/128_2007_20.

Solid State NMR Structure Analysis of the Antimicrobial Peptide Gramicidin S in Lipid Membranes: Concentration-Dependent Re-alignment and Self-Assembly as a β-Barrel.

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Karlsruhe Institute of Technology (KIT), Institut für Biologische Grenzflächen, PO Box 3640, 76021, Karlsruhe, Germany.


Antimicrobial peptides can kill bacteria by permeabilizing their cell membrane, as these amphiphilicmolecules interact favourably with lipid bilayers. This mechanism of action is attributed eitherto the formation of a peptide "carpet" on the membrane surface, or to a transmembranepore. However, the structure of such a pore has not yet been resolved under relevant conditions.Gramicidin S is a symmetrical cyclic β-sheet decapeptide, which has been previouslyshown by solid state NMR to lie flat on the membrane surface at low peptide:lipid ratios (≤ 1:80).Using highly sensitive (19)F-NMR, supported by (15)N-labelling,we found that gramicidin S can flip into an upright transmembrane alignment at high peptide:lipidratios (≥ 1:40). Orientational NMR constraints suggest that the peptide may self-assembleas an oligomeric β-barrel pore, which is stabilized by intermolecular hydrogen bonds. Comparisonof different model membranes shows that the observed re-alignment is favoured in thin bilayers withshort-chain lipids, especially near the chain melting temperature, whereas long-chain lipids suppresspore formation. Based on the oligomeric structural model and the conditions of pore formation, guidelinesmay now be derived for rationally designing peptide analogues as antibiotics with improved selectivityand reduced side effects.


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