THE PORE DOMAIN OF THE NICOTINIC ACETYLCHOLINE-RECEPTOR - MOLECULAR MODELING, PORE DIMENSIONS, AND ELECTROSTATICS

The pore domain of the nicotinic acetylcholine receptor has been model ed as a bundle of five kinked M2 helices. Models were generated via mo lecular dynamics simulations incorporating restraints derived from 9-A ngstrom resolution cryoelectron microscopy data (Unwin, 1993; 1995), a nd from mutagenesis data that identify channel-lining side chains. Thu s, these models conform to current experimental data but will require revision as higher resolution data become available. Models of the ope n and closed states of a homopentameric alpha 7 pore are compared. The minimum radius of the closed-state model is less than 2 Angstrom; the minimum radius of the open-state model is similar to 6 Angstrom. It i s suggested that the presence of ''bound'' water molecules within the pore may reduce the effective minimum radii below these values by up t o similar to 3 Angstrom. Poisson-Boltzmann calculations are used to ob tain a first approximation to the potential energy of a monovalent cat ion as it moves along the pore axis. The differences in electrostatic potential energy profiles between the open-state models of alpha 7 and of a mutant of alpha 7 are consistent with the experimentally observe d change in ion selectivity from cationic to anionic. Models of the op en state of the heteropentameric Torpedo nicotinic acetylcholine recep tor pore domain are also described. Relatively small differences in po re radius and electrostatic potential energy profiles are seen when th e Torpedo and alpha 7 models are compared.