Molecular dynamics simulations of a K channel model: Sensitivity to changes in ions, waters, and membrane environment

Biological ion channels are protein pores of sub-nanometer radius that enable rapid movement of selected ions across membranes. K channels are selective for K+ over Na+ ions, a function that resides in a narrow selectivity filter at the extracellular end of the channel. A model of an inward rectifier (Kir)., derived from the structure of the bacterial channel KcsA, has been used in multi-nanosecond MD simulations to explore the conformational dynamics of the channel under different simulation conditions. Different simulation conditions were compared: a lipid bilayer vs a membrane-mimetic octane slab, different numbers of water molecules in the central channel cavity, and K+ vs Na+ ions in the selectivity filter of the channel. Structural drift from the initial model was small, and there was little effect of simulation conditions on this drift. In a long (10 ns) simulation it was shown that significant conformational changes were restricted to the water-exposed loops while the core transmembrane structure remained unchanged. A flexibility gradient was observed in the channel molecule along the channel axis, with flexibility increasing from the extracellular to the intracellular end. This correlates with biological function, ion selectivity being located in the filter at the extracellular end of the molecule, whereas gating is thought to be located at the intracellular mouth of the channel. Examination of the dynamics of ions and water molecules in the filter revealed relaxation of the K+-water-K+ single file to a preferred 0101 configuration on a I ns time scale. On a longer (10 ns) time scale K+ ions were seen to fully traverse the filter, and to exit/reenter relative to the central cavity. The filter was shown to be flexible, both in terms of fluctuations in its radius profile and in terms of local changes in conformation in response to ion translocation. Na+ ions resulted in a narrowing of the filter compared to K+ ions. Na+ ions occupied slightly different sites in the filter, and exhibited octahedral coordination (four filter oxygens + two water oxygens) rather than the cubic coordination (by eight filter oxygens) preferred by K+ ions.