The Role of Proton Transport in Gating Current in a Voltage Gated Ion Channel, as Shown by Quantum Calculations

Alisher M Kariev; Michael E Green

Understanding the gating mechanism (how the channel opens and closes) requires structures. One TM segment (S4) has an arginine in every third position, with one such segment per domain. It is usually assumed that these arginines are all ionized, and in the resting state are held toward the intracellular side of the membrane by voltage across the membrane. They are assumed to move outward (extracellular direction) when released by depolarization of this voltage, producing a capacitive gating current and opening the channel. We suggest alternate interpretations of the evidence that led to these models. Measured gating current is the total charge displacement of all atoms in the VSD; we propose that the prime, but not sole, contributor is proton motion, not displacement of the charges on the arginines of S4. It is known that the VSD can conduct protons. Quantum calculations on the K v 1.2 potassium channel VSD show how; the key is the amphoteric nature of the arginine side chain, which allows it to transfer a proton; this appears to be the first time the arginine side chain has had its amphoteric character considered. We have calculated one such proton transfer in detail: this proton starts from a tyrosine that can ionize, transferring to the NE of the third arginine on S4; that arginine's We will primarily discuss the 3Lut (pdb code) structure of the K v 1.2 channel, for which the hydrogens were added by normal mode analysis (19) . Fig. 1 shows the structure of the full channel, reproduced from the pdb website. Our calculations are so far limited to a large part of just one VSD. The calculations show the path for a proton through the section that has been calculated, with no water involved. However, once one gets past the hydrophobic section, there is water in the remainder of the path to the gate. This part has not yet been computed, but we can see what appears to be a clear pathway, and propose it as a hypothesis.