MODELING AND SIMULATION OF ION CHANNELS - APPLICATIONS TO THE NICOTINIC ACETYLCHOLINE-RECEPTOR

Molecular dynamics simulations with experimentally derived restraints have been used to develop atomic models of M2 helix bundles forming th e pore-lining domains of the nicotinic acetylcholine receptor and rela ted ligand-gated ion channels. M2 helix bundles have been used in micr oscopic simulations of the dynamics and energetics of water and ions w ithin an ion channel. Translational and rotational motion of water are restricted within the pore, and water dipoles are aligned relative to the pore axis by the surrounding helix dipoles. Potential energy prof iles for translation of a Na+ ion along the pore suggest that the prot ein and mater components of the interaction energy exert an opposing e ffect on the ion, resulting in a relatively hat profile which favors c ation permeation. Empirical conductance calculations based on a pore r adius profile suggest that the M2 helix model is consistent with a sin gle channel conductance of ca. 50 pS. Continuum electrostatics calcula tions indicate that a ring of glutamate residues at the cytoplasmic mo uth of the alpha 7 nicotinic receptor M2 helix bundle may not be fully ionized. A simplified model of the remainder of the channel protein w hen added to the M2 helix bundle plays a significant role in enhancing the ion selectivity of the channel. (C) 1998 Academic Press.