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Abstract

Potassium channels have been called Nature's transistors and diodes. These tetrameric membrane proteins act as control valves that regulate the flux of \pot ions crossing the lipid bilayer of a cell. Sometimes the electrical signals generated by an open potassium channel will mysteriously terminate, a process that has been named inactivation. Several distinct mechanisms can underlie the loss of current, one of them being a conformational change in a part of the channel called the selectivity filter. Once the selectivity filter has become inactivated, the block will remain present for a prolonged period of time that can last for tens of seconds. X-ray crystallographic structures of the bacterial channel KcsA have revealed both conductive and non-conductive conformations of the selectivity filter, the latter of which have been speculated to represent the inactivated state. However, only a slight \about 1 \AA \ pinching motion at the center of the selectivity filter occurs in the non-conductive structures, raising the question of how such a small conformational change can explain the long timescales associated with inactivation. Using Molecular Dynamics simulations, it has been discovered that water molecules may become buried behind the selectivity filter locking the filter in the non-conductive conformation. Only when all the water molecules leave may the selectivity filter return to a conductive state. Because it would be an extremely rare event for all the buried water molecules to leave and not return, the non-conductive conformation is expected to persist for a lengthy period of time on par with that of inactivation. To claim that the non-conductive conformation represents the inactivated state, it is necessary to recreate the conditions that favor inactivation. Two factors that destabilize the conductive selectivity filter and promote inactivation are (i) simply holding the channel open or (ii) decreasing the extracellular potassium concentration. Under either of these conditions, Molecular Dynamic simulations starting with the selectivity filter in a conductive conformation reveal it making a transition to the non-conductive state. In contrast, the selectivity filter remains conductive when the conditions are absent. Water molecules penetrating behind the selectivity filter appear to catalyze the transition. Before each spontaneous transition water molecules enter the protein behind the filter. Removing the water molecules causes the filter to immediately return to a conductive conformation. The results reinforce the view that the non-conductive conformation of the selectivity filter represents the inactivated state and highlights the role that water molecules throughout the inactivation process.

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