MOLECULAR-DYNAMICS STUDY OF WATER AND NA-RECEPTOR( IONS IN MODELS OF THE PORE REGION OF THE NICOTINIC ACETYLCHOLINE)

The nicotinic acetylcholine receptor (nAChR) is an integral membrane p rotein that forms ligand-gated and cation-selective channels. The cent ral pore is lined by a bundle of five approximately parallel M2 helice s, one from each subunit. Candidate model structures of the solvated p ore region of a homopentameric (alpha 7)(5) nAChR channel in the open state, and in two possible forms of the closed state, have been studie d using molecular dynamics simulations with restraining potentials. It is found that the mobility of the water is substantially lower within the pore than in bulk, and the water molecules become aligned with th e M2 helix dipoles. Hydrogen-bonding patterns in the pore, especially around pore-lining charged and hydrophilic residues, and around expose d regions of the helix backbone, have been determined. Initial studies of systems containing both water and sodium ions together within the pore region have also been conducted. A sodium ion has been introduced into the solvated models at various points along the pore axis and it s energy profile evaluated. it is found that the ion causes only a loc al perturbation of the water structure. The results of these calculati ons have been used to examine the effectiveness of the central ring of leucines as a component of a gate in the closed-channel model.