Homology modeling and molecular dynamics simulation studies of an inward rectifier potassium channel

A homology model has been generated for the pore-forming domain of Kir6.2, a component of an ATP-sensitive K channel, based on the x-ray structure of the bacterial channel KcsA, Analysis of the lipid-exposed and pore-lining s urfaces of the model reveals them to be compatible with the known features of membrane proteins and Kir channels, respectively. The Kir6.2 homology mo del was used as the starting point for nanosecond-duration molecular dynami cs simulations in a solvated phospholipid bilayer. The overall drift from t he model structure was comparable to that seen for KcsA in previous similar simulations. Preliminary analysis of the interactions of the Kir6.2 channe l model with K+ ions and water molecules during these simulations suggests that concerted single-file motion of K+ ions and water through the selectiv ity filter occurs. This is similar to such motion observed in simulations o f KcsA. This suggests that a single-filing mechanism is conserved between d ifferent K channel structures and may be robust to changes in simulation de tails. Comparison of Kir6.2 and KcsA suggests some degree of flexibility in the filter, thus complicating models of ion selectivity based upon a rigid filter.