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Interactions of the M2 Segment of the Acetylcholine Receptor with Lipid Bilayers: A Continuum-Solvent Model Study

Amit Kessel ^*, Turkan Haliloglu  and Nir Ben-Tal ^*

^* Department of Biochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Israel; and Polymer Research Center and Chemical Engineering Department, Bogazici University, Bebek-Istanbul, Turkey

Correspondence: Address reprint requests to Nir Ben-Tal, Dept. of Biochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, Israel. Tel.: 972-3-640-6709; Fax: 972-3-640-6834; E-mail: bental{at}ashtoret.tau.ac.il.

M2, one of the transmembrane segments of the nicotinic acetylcholine receptor, is a 23-amino-acid peptide, frequently used as a model for peptide-membrane interactions. In this and the companion article we describe studies of M2-membrane interactions, using two different computational approaches. In the present work, we used continuum-solvent model calculations to investigate key thermodynamic aspects of its interactions with lipid bilayers. M2 was represented in atomic detail and the bilayer was represented as a hydrophobic slab embedded in a structureless aqueous phase. Our calculations show that the transmembrane orientation is the most favorable orientation of the peptide in the bilayer, in good agreement with both experimental and computational data. Moreover, our calculations produced the free energy of association of M2 with the lipid bilayer, which, to our knowledge, has not been reported to date. The calculations included 10 structures of M2, determined by nuclear magnetic resonance in dodecylphosphocholine micelles. All the structures were found to be stable inside the lipid bilayer, although their water-to-membrane transfer free energies differed by as much as 12 kT. Although most of the structures were roughly linear, a single structure had a kink in its central region. Interestingly, this structure was found to be the most stable inside the lipid bilayer, in agreement with molecular dynamics simulations of the peptide and with the recently determined structure of the intact receptor. Our analysis showed that the kink reduced the polarity of the peptide in its central region by allowing the electrostatic masking of the Gln13 side chain in that area. Our calculations also showed a tendency for the membrane to deform in response to peptide insertion, as has been previously found for the membrane-active peptides alamethicin and gramicidin. The results are compared to Monte Carlo simulations of the peptide-membrane system, as presented in the accompanying article.

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Interactions of Hydrophobic Peptides with Lipid Bilayers: Monte Carlo Simulations with M2

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