K+ in a Kv1.2 Channel Pore: Hydration, Selectivity, and the Role of a Conserved Threonine

Quantum calculations describing transport of K+ through a Kv1.2 channel cavity, plus the lower half of the selectivity filter (SF), show hydration in the pore and cosolvation by threonine at the entrance to the SF. Comparison to calculations on Na+ ions gives the probable selectivity mechanism. A single K+ ion is calculated at five positions in its course through the cavity, and two ions calculated at three positions at the entrance to the SF. Three Na+ pairs of ions were also calculated, and one shows how an ion is trapped asymmetrically, tightly held by two threonine -OH, and with a water tightly bound ahead of it, so that overall it has a major barrier to advancing, while K+ advances with minimal barriers. In the cavity below the SF, the ion passes in a hydrated state through pore water, between the intracellular gate and the SF, until it is cosolvated by the threonines at the selectivity filter entrance. These calculations show how the ion associates with the water, and enters the SF. A characteristic arrangement of four water molecules adjacent to the SF in the KcsA channel, shown in earlier work, is now found in Kv1.2. A single ion passing through the channel cavity is found to have an energy minimum within 1 [A] of the K+ ion position in the 3Lut pdb structure of this channel. Properties (e.g. dipole moment) of the system are calculated. Charge transfer to the ion produces K+ charge 0.74 [≤] q(ion) [≤] 0.87 e, in different conditions. The calculations of pairs of Na+ and K+ ions at the SF entrance include the threonine, valine, and glycine of the conserved SF TVGYG sequence. The Na+/K+ difference shows a reason for the conservation of the threonine in producing selectivity, as the -OH groups trap Na+ but not K+.\n\nSTATEMENT OF SIGNIFICANCEPotassium channels are found in all cells, and have a characteristic selectivity filter that blocks the passage of Na+ while allowing K+ to pass. These channels are implicated in many diseases. We use quantum calculations to show how the K+ ion passes from the intracellular gate of the channel, entering the channel pore, to the selectivity filter at the extracellular end of the channel; at the selectivity filter, we use comparable calculations of K+ and Na+ to show how the channel selects K+ over Na+, as well as the probable reason for the conservation of a key residue (threonine) at the base of the selectivity filter. We find properties (e.g., charge transfer, bond order) that require quantum calculations.