2H-NMR and MD Simulations Reveal Membrane-Bound Conformation of Magainin 2 and Its Synergy with PGLa
| Autor: | Jonathan Zerweck, Erik Strandberg, Parvesh Wadhwani, Diana Horn, Sabine Reißer, Anne S. Ulrich |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Membranes Biophysics Magainin Nuclear magnetic resonance spectroscopy 010402 general chemistry 01 natural sciences 0104 chemical sciences 03 medical and health sciences chemistry.chemical_compound Crystallography Molecular dynamics 030104 developmental biology Membrane chemistry Helix Lipid bilayer POPC Alpha helix |
| Zdroj: | Biophysical Journal. 111:2149-2161 |
| ISSN: | 0006-3495 |
| DOI: | 10.1016/j.bpj.2016.10.012 |
| Popis: | Magainin 2 (MAG2) and PGLa are two α-helical antimicrobial peptides found in the skin of the African frog Xenopus laevis. They act by permeabilizing bacterial membranes and exhibit an exemplary synergism. Here, we determined the detailed molecular alignment and dynamical behavior of MAG2 in oriented lipid bilayers by using 2H-NMR on Ala-d3-labeled peptides, which yielded orientation-dependent quadrupolar splittings of the labels. The amphiphilic MAG2 helix was found to lie flat on the membrane surface in 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC)/1,2-dimyristoyl-sn-glycero-3-phosphatidylglycerol (DMPG) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC)/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylglycerol (POPG), as expected, with a tilt angle close to 90°. This orientation fits well with all-atom molecular-dynamics simulations of MAG2 performed in DMPC and DMPC/DMPG. In the presence of an equimolar amount of PGLa, the NMR analysis showed that MAG2 becames tilted at an angle of 120°, and its azimuthal rotation angle also changes. Since this interaction was found to occur in a concentration range where the peptides per se do not interact with their own type, we propose that MAG2 forms a stable heterodimer with PGLa. Given that the PGLa molecules in the complex are known to be flipped into a fully upright orientation, with a helix tilt close to 180°, they must make up the actual transmembrane pore. We thus suggest that the two negative charges on the C-terminus of the obliquely tilted MAG2 peptides neutralize some of the cationic groups on the upright PGLa helices. This would stabilize the assembly of PGLa into a toroidal pore with an overall reduced charge density, which could explain the mechanism of synergy. |
| Databáze: | OpenAIRE |
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