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Pores Formed by the Nicotinic Receptor M2 Peptide: A Molecular Dynamics Simulation Study

R. J. Law^*, D. P. Tieleman and M. S. P. Sansom^*

^* Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom; and Department of Biological Sciences, University of Calgary, Calgary, Alberta T2N 1N4, Canada

Correspondence: Address reprint requests to M. S. P. Sansom. Tel: +44-1865-275371; Fax: +44-1865-275182; E-mail: mark{at}biop.ox.ac.uk.

The M2 peptide self-assembles to form a pentameric bundle of transmembrane -helices that is a model of the pore-lining region of the nicotinic acetylcholine receptor. Long (>15 ns) molecular dynamics simulations of a model of the M2₅ bundle in a POPC bilayer have been used to explore the conformational dynamics of the channel assembly. On the timescale of the simulation, the bundle remains relatively stable, with the polar pore-lining side chains remaining exposed to the lumen of the channel. Fluctuations at the helix termini, and in the helix curvature, result in closing/opening transitions at both mouths of the channel, on a timescale of 10 ns. On average, water within the pore lumen diffuses 4x more slowly than water outside the channel. Examination of pore water trajectories reveals both single-file and path-crossing regimes to occur at different times within the simulation.

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