Solid-State NMR Analysis Comparing the Designer-Made Antibiotic MSI-103 with Its Parent Peptide PGLa in Lipid Bilayers
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- 作者：Erik Strandberg ; Nathalie Kanithasen ; Deniz Tiltak ; Jochen Bü ; rck ; Parvesh Wadhwani ; Olaf Zwernemann ; Anne S. Ulrich
- 刊名：Biochemistry
- 出版年：2008
- 出版时间：February 26, 2008
- 年：2008
- 卷：47
- 期：8
- 页码：2601 - 2616
- 全文大小：849K
- 年卷期：v.47,no.8(February 26, 2008)
- ISSN：1520-4995
文摘
The amphiphilic 
-helical peptide (KIAGKIA)3-NH2 (MSI-103) is a designer-made antibiotic,based on the natural sequence of PGLa from Xenopus laevis. Here, we have characterized the concentration-dependent alignment and dynamic behavior of MSI-103 in lipid membranes by solid-state 2H and 19FNMR, using orientational constraints from seven Ala-d3-labeled analogues and five 4-CF3-phenylglycinelabels. As previously found for PGLa, MSI-103, too, assumes a flat surface-bound S-state alignment atlow peptide concentrations, and it also realigns to a tilted T-state at higher concentrations. For PGLa, thestability of the T-state had been attributed to the specific assembly of antiparallel dimers; hence, it isremarkable that the artificial KIAGKIA repeat sequence can also dimerize in the same way in liquidcrystalline lipid bilayers. Oriented circular dichroism analysis shows that for MSI-103 the threshold forrealignment from the S-state to the T-state is ~3-fold lower than for PGLa (at a peptide-to-lipid ratio of1:240 in dimyristoylphosphatidylcholine, compared to 1:80). Furthermore, MSI-103 becomes laterallyimmobilized in the lipid bilayer at a concentration ratio of 1:50, which occurs for PGLa only above 1:20.The superior antimicrobial activity of MSI-103 over PGLa thus appears to correlate with its strongertendency to realign and self-assemble. The hemolytic activities of MSI-103 and its analogues, on theother hand, are shown here to correlate purely with the respective changes in hydrophobicity.
-helical peptide (KIAGKIA)3-NH2 (MSI-103) is a designer-made antibiotic,based on the natural sequence of PGLa from Xenopus laevis. Here, we have characterized the concentration-dependent alignment and dynamic behavior of MSI-103 in lipid membranes by solid-state 2H and 19FNMR, using orientational constraints from seven Ala-d3-labeled analogues and five 4-CF3-phenylglycinelabels. As previously found for PGLa, MSI-103, too, assumes a flat surface-bound S-state alignment atlow peptide concentrations, and it also realigns to a tilted T-state at higher concentrations. For PGLa, thestability of the T-state had been attributed to the specific assembly of antiparallel dimers; hence, it isremarkable that the artificial KIAGKIA repeat sequence can also dimerize in the same way in liquidcrystalline lipid bilayers. Oriented circular dichroism analysis shows that for MSI-103 the threshold forrealignment from the S-state to the T-state is ~3-fold lower than for PGLa (at a peptide-to-lipid ratio of1:240 in dimyristoylphosphatidylcholine, compared to 1:80). Furthermore, MSI-103 becomes laterallyimmobilized in the lipid bilayer at a concentration ratio of 1:50, which occurs for PGLa only above 1:20.The superior antimicrobial activity of MSI-103 over PGLa thus appears to correlate with its strongertendency to realign and self-assemble. The hemolytic activities of MSI-103 and its analogues, on theother hand, are shown here to correlate purely with the respective changes in hydrophobicity.