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Interaction between peptide pores in lipid bilayers

The elucidation of lipid-mediated interaction forces between membrane proteins and the corresponding lateral distribution in the plane of the membrane is an important step towards a quantitative understanding of the functional mechanisms of membrane proteins and membrane peptides. Experimentally, the lateral structure and organization of multi-component membranes is as important as it is difficult to probe. In this work we show how the lateral and vertical intensity profiles of a peptide pore correlation peak can be analyzed as a function of peptide concentration to determine the corresponding interaction forces.

A well-known example of biological function deriving from lipid-peptide interaction and self-assembly is the activity of a family of short and amphiphilic membrane active polypeptides denoted as antimicrobial peptides. These molecules bind to microbial cell membranes, subsequently causing an increase in membrane permeability and cell lysis. One such molecule is alamethicin, a 20 amino acid peptide from the fungus Trichoderma viride; it is well known that alamethicin acts by creating pores in the cell membrane. Pore formation is usually a highly cooperative process; this was confirmed for alamethicin and a membrane-mediated interaction between peptides was invoked to explain the phenomenon.

Figure 1: Structure of the alamethicin pore (from [1]). Top view (left) and side view (center). Electron density profile (right) reconstructed from the atomic coordinates of an MD simulation [2].


Although determining the interaction between (adsorbed or inserted) monomers is very difficult and, to our knowledge, has never been attempted, the interaction between already formed pores within the membrane can be studied using neutron or X-ray scattering from oriented multilamellar stacks, a method pioneered by Huang and collaborators [3-5]. For the case of alamethicin, they observed a lateral correlation peak, which was attributed to liquid-like ordering of pores in the plane of the membrane and was modeled based on hard disk interaction, with very satisfactory results. However, in theses studies at most two peptide-to-lipid concentrations P/L were investigated for each system.

Building upon this work, we gathered detailed information on the quasi two-dimensional fluid of pores in the lipid bilayer, using high-resolution synchrotron scattering from aligned multilamellar stacks of alamethicin/DMPC mixtures. We measured the two-dimensional scattering distribution for an entire concentration series P/L and performed a simultaneous lineshape analysis on all recorded curves.

We found that the in-plane interaction potential consists of a hard core, with a radius that agrees very well with the geometrical outer radius of the pore, and an additional repulsive contribution which can be described as a Gaussian, with a range of 31.5 Å and a contact value of 2.41 kBT. The results are in qualitative agreement with recent theoretical models [6-7].

Figure 2: a) Scattering from the 2D fluid of alamethicin pores as a function of the wave vector for different peptide-to-lipid concentrations (symbols) and fit with the theoretical model (lines). b) The interaction potential used for the fits in a). It consists of a hard core with a diameter 2R = 36.4 Å and an additional Gaussian repulsion (see text). c) Pictorial representation of the fluid of pores in the plane of the bilayer: the alamethicin monomers are in red, the inner water pore in blue and the repulsive potential is depicted as a gray halo.



[1] Spaar, A. 2003. The Structure of Lipid Membranes and the Conformation of Peptides in Membranes Studied by Surface X-Ray Scattering, PhD Thesis, Saarbrücken University.

[2] Tieleman, D. P., H. J. C. Berendsen, and M. S. P. Sansom. 1999. An alamethicin channel in a lipid bilayer: Molecular dynamics simulations. Biophysical Journal 76, 1757-1769.

[3] He, K., S. J. Ludtke, H. W. Huang, and D. L. Worcester. 1995. Antimicrobial peptide pores in membranes detected by neutron in-plane scattering. Biochemistry 34, 15614-15618.

[4] He, K., S. J. Ludtke, D. L. Worcester, and H. W. Huang. 1996. Neutron scattering in the plane of the membranes: Structure of alamethicin pores. Biophysical Journal 70, 2659-2666.

[5] Yang, L., T.Weiss, T. Harroun, W. Heller, and H. Huang. 1999. Supramolecular structures of peptide assemblies in membranes by neutron off-plane scattering: Method of analysis. Biophysical Journal 77, 2648-2656.

[6] Lagüe, P., M. J. Zuckermann, and B. Roux. 2000. Lipid-mediated interactions between intrinsic membrane proteins: A theoretical study based on integral equations. Biophysical Journal 79, 2867-2879.

[7] Lagüe, P., M. J. Zuckermann, and B. Roux. 2001. Lipid-mediated interactions between intrinsic membrane proteins: Dependence on protein size and lipid composition. Biophysical Journal 81, 276-284.



Interaction of Alamethicin Pores in DMPC Bilayers
Biophysical Journal 92, 3978–3987 (2007)


Doru Constantin - Laboratoire de Physique des Solides, Orsay (France).
Guillaume Brotons - Laboratoire de Physique de l’État Condensé, Le Mans (France).
Ansgar Jarre, Chenghao Li and Tim Salditt - Institut für Röntgenphysik, Göttingen (Germany).