WATER AND H+ TRANSFER IN VOLTAGE GATED K+ CHANNEL FUNCTION, WITH EVIDENCE FROM QUANTUM CALCULATIONS.

Voltage gated K⁺ channels have been the subject of intensive study for over a half century. They are found in all cells; together with Na⁺ channels, they are responsible for the nerve impulse, and play a key role in other excitable tissue, particularly the heart. Malfunctions due to mutation lead to a range of diseases, referred to as channelopathies. The mechanism by which the channels open and close, called gating, has been studied extensively; there is a range of standard models. All have in common a transmembrane segment of the channel protein moving in response to depolarization of the membrane, thereby pulling open a section of the channel at the intracellular end of the membrane; this allows K⁺ ions into the channel pore, producing a current of ions out from the cell. The motion of the ions is preceded by a capacitative current, the gating current, which is attributed to positive charges on the putatively mobile transmembrane segment. The evidence supporting this class of models is examined and reinterpreted to show that the evidence does not require the motion of a segment of protein. This and other evidence is instead considered in terms of a model in which protons provide the gating current; when these are at the intracellular terminus of the protein, they close the channel, while the channel is open when they are at the extracellular end. This model is supported by quantum calculations that are larger than have been previously reported for a protein system. Some of the calculations include most of the voltage sensing domain, and others the pore of the channel, with the hydration and cosolvation of the ion specified.