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The Transmembrane Domain of the Acetylcholine Receptor: Insights from Simulations on Synthetic Peptide Models

Leonor Saiz ^*  and Michael L. Klein ^*

^* Center for Molecular Modeling, Chemistry Department, University of Pennsylvania, Philadelphia, Pennsylvania 19104; and Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Correspondence: Address reprint requests to Leonor Saiz, E-mail: leonor{at}sas.upenn.edu or leonor{at}cbio.mskcc.org.

We have studied the structure and properties of a bundle of -helical peptides embedded in a 1,2-dimyristoyl-3-phosphatidylcholine phospholipid bilayer by molecular dynamics simulations. The bundle of five transmembrane M2 segments constitutes the model for the pore region of the nicotinic acetylcholine receptor, which is the neurotransmitter-gated ion-channel responsible for the fast propagation of electrical signals between cells at the nerve-muscle synapse. The M2 segments were shown to oligomerize in biomembranes resulting in ion-channel activity with characteristics similar to the native protein, and the structure of the isolated peptides was studied in 1,2-dimyristoyl-3-phosphatidylcholine bilayers and micelles by NMR experiments (Opella, S. J., et al. 1999. Nat. Struct. Biol. 6:374–379). Our analyses indicate that the structure, helix tilt, and the overall shape of the channel are in good agreement with the NMR experiments and the proposed model for the channel, which we show is formed by rings of functional residues. The studied geometry resulted in a closed pore state, where the channel is partially dehydrated at the hydrophobic extracellular half and the extracellular mouth of the channel blocked by the hydrocarbon chains of Arg⁺ residues. The arginine amino acids form intermolecular salt-bridges with the C-terminus, which contribute as well to the bundle stabilization.

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