| Abstract: |
We have studied the structure and properties of a bundle of α-helical peptides embedded in a 1,2-dimyristoyl-3-phosphatidylcholine phospholipid bilayer by molecular dynamics simulations. The bundle of five transmembrane δM2 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 δM2 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. © 2005 by the Biophysical Society. |
| Keywords: |
nonhuman; comparative study; protein conformation; protein domain; carboxy terminal sequence; molecular dynamics; protein binding; protein stability; validation study; peptide; structure activity relation; structure-activity relationship; simulation; chemistry; evaluation; peptides; magnetic resonance spectroscopy; nuclear magnetic resonance spectroscopy; binding site; computer simulation; models, molecular; protein structure, tertiary; binding sites; chemical structure; porosity; protein structure; ultrastructure; protein tertiary structure; models, chemical; oligomerization; molecular model; lipid bilayers; lipid bilayer; arginine; membranes, artificial; cholinergic receptor; synthetic peptide; membrane; nicotinic receptor; alpha helix; chemical model; membrane fluidity; hydrophobicity; micelle; neurotransmitter; ion channel; channel gating; ion channel gating; hydrocarbon; receptors, nicotinic; dimyristoylphosphatidylcholine; artificial membrane; phospholipid bilayer
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