Ligand-gated transport of cations through the nicotinic acetylcholine receptor (nAChR) transmembrane protein is important for a variety of cognitive functions, and nAChR dysfunction has been implicated in diseases ranging from epilepsy and schizophrenia to Alzheimer's and Parkinson's disease. We have used molecular dynamics and adaptive biasing force simulations to study the structure of the transmembrane domain of nAChR and the energetics, mechanism, and dynamics of ion transport, both for the wild type and two physiologically relevant mutants. Water structure is crucial in understanding ion transport, as the cation cannot maintain a fully hydration shell while transiting the channel. Large-scale helical motions were associated with channel opening; these observations are significant given the absence of an experimentally determined structure of the channel in the open state. Both the geometry and the potential of mean force for sodium ion translocation indicate a bottleneck in the native structure that is consistent with previous experimental findings. Ion permeation was studied at a range of electric field values above physiological values, at which we could observe statistically significant numbers of ion crossing events, and which still allowed extrapolation to physiological conditions.The L251T mutant had the effect of widening the channel, reducing the free energy barrier to sodium ion translocation, and increasing ion current relative to the native state, while the T248F mutant had the opposite effect. These mutations in the protein did not change the hydration state of the channel lumen substantially, but significant changes were seen in the hydration shell of the cation when transiting the bottleneck region.

Modeling ion permeation in wild-type and mutant human a7 nicotinic acetylcholine receptor ion channels

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.