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. 2008 Oct;95(8):3840-9.
doi: 10.1529/biophysj.107.128322. Epub 2008 May 30.

Surfactin-triggered small vesicle formation of negatively charged membranes: a novel membrane-lysis mechanism

Sébastien Buchoux  1 , Joséphine Lai-Kee-Him, Marie Garnier, Pascale Tsan, Françoise Besson, Alain Brisson, Erick J Dufourc
Affiliations

Surfactin-triggered small vesicle formation of negatively charged membranes: a novel membrane-lysis mechanism

Sébastien Buchoux et al. Biophys J. 2008 Oct.

Abstract

The molecular mode of action of the lipopeptide SF with zwitterionic and negatively charged model membranes has been investigated with solid-state NMR, light scattering, and electron microscopy. It has been found that this acidic lipopeptide (negatively charged) induces a strong destabilization of negatively charged micrometer-scale liposomes, leading to the formation of small unilamellar vesicles of a few 10s of nanometers. This transformation is detected for very low doses of SF (Ri = 200) and is complete for Ri = 50. The phenomenon has been observed for several membrane mixtures containing phosphatidylglycerol or phosphatidylserine. The vesicularization is not observed when the lipid negative charges are neutralized and a cholesterol-like effect is then evidenced, i.e., increase of gel membrane dynamics and decrease of fluid membrane microfluidity. The mechanism for small vesicle formation thus appears to be linked to severe changes in membrane curvature and could be described by a two-step action: 1), peptide insertion into membranes because of favorable van der Waals forces between the rather rigid cyclic and lipophilic part of SF and lipid chains and 2), electrostatic repulsion between like charges borne by lipid headgroups and the negatively charged SF amino acids. This might provide the basis for a novel mode of action of negatively charged lipopeptides.

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Figures

FIGURE 1
FIGURE 1
SF primary structure from Peypoux et al. (9). Alkyl chain in position 8 and amino acids at positions 2, 4, and 7 are variable depending on isoforms. Structure for the this study: 1Glu(L)Leu(L)Leu(D)Val(L)Asp(L)Leu(D)Leu(L)7-isoC14, MW 1036.34.
FIGURE 2
FIGURE 2
SF effect on DMPC-2H27 MLV (20 mg in 100 μL). 2H-NMR spectra are shown at 18°C, 21°C, and 39°C, in the absence of SF (left) and with SF incorporated (Ri = 25, right). Number of acquisitions = 2k, 50-Hz Lorentzian filtering.
FIGURE 3
FIGURE 3
SF effect on DMPG-2H27/SM (1:1 molar ratio) and DMPC-2H27/DMPG (1:1 molar ratio) systems (20 mg total lipids in 100 μL). 2H-NMR spectra are shown at 18°C and 39°C, in the absence (left) and in the presence of SF (right, Ri = 50). NMR conditions as in Fig. 2.
FIGURE 4
FIGURE 4
SF effect on DMPC-2H27/DMPS (1:1 molar ratio) system at pH 7.5 (top) and pH 4.5 (bottom), (20 mg total lipids in 100 μL). 2H-NMR spectra are shown at 18°C and 39°C, in the absence (left) and in the presence of SF (right, Ri = 50). NMR conditions as in Fig. 2.
FIGURE 5
FIGURE 5
Temperature dependence of M1 calculated for DMPC-2H27/DMPS (1:1 molar ratio) spectra at pH 4.5 without SF (squares) and with SF (Ri = 50, triangles). (Inner graph) SCD profile calculated for de-Paked spectra (see text) at T = 34°C. Labeled carbon positions were assigned according to the literature. Experimental error is in symbol size.
FIGURE 6
FIGURE 6
SF effect on DMPC/DMPG (1:1 molar ratio) systems (20 mg total lipids in 100 μL). 31P-NMR spectra are shown at 18°C and 39°C, with increasing amounts of SF from top to bottom. Number of acquisitions = 1k, 50-Hz Lorentzian filtering.
FIGURE 7
FIGURE 7
Effect of SF on the hydrodynamic radius of DMPC/DMPG (1:1 molar ratio) MLV, as monitored by DLS. Lipid/peptide molar ratios are shown on graphs. Temperature was regulated at 25°C.
FIGURE 8
FIGURE 8
TEM images of SF and of DMPC/DMPG (1:1 molar ratio) without and with lipopeptide, using negative staining (A, B, and C) and cryo-TEM (D). (A) SF micelles, bar: 100 nm. (B) MLV in the absence of peptide, bar = 200 nm. (C) With SF, Ri = 50, bar: 200 nm. (D) Same as C observed using cryo-TEM, bar: 25 nm.
FIGURE 9
FIGURE 9
Artist view illustrating the “wedge-repulsion” model: SF molecules penetrate into the hydrophobic core of membranes because of favorable hydrophobic forces, and an electrostatic repulsion occurs between negative charges of peptidic amino acids Glu/Asp and negatively charged lipid headgroups. This promotes an increase in local membrane curvature, which destabilizes MLV (A) to form SUVs (B).
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