A model for ion channel voltage gating with static S4 segments

The voltage gated ion channels (especially for Na+ and K+, with several Ca2 + channels being closely related) of nerve and other membranes have been in tensively studied for over 50 years; the gating mechanism is now being work ed out, using several different lines of evidence. While the amino acid seq uence of the protein which makes up the channels is known, and numerous sit es have been mutated, with the mutations studied in a number of ways, there are still fundamental disagreements on the details of the gating mechanism . The protein is a tetramer (approximately), each domain having six transme mbrane segments, with the fourth (S4) containing basic amino acids at every third position; the most common mechanism which has been proposed is to ha ve S4 move some distance through the membrane, in the process opening the c hannel. We wish to propose a different mechanism, in which S4 remains stati onary (or almost so). The "gate" is water, held in the pore by hydrogen bon ding and by fields of the charges on amino acid side chains. To test this s uggestion, we have done calculations which give an estimate of the distribu tion of the electric field in the water filled pore, Monte Carlo simulation s of the behavior of the water in the pore, and ab initio proton tunneling calculations of a model system; we suggest the mechanism for the first step in gating charge motion may be tunneling of a proton. The local field may reach 10(9)Vm(-1), and the transmembrane held 10(7) Vm(-1), which are criti cal for the tunneling. Based on the electric potential calculations, we pro pose that not all the S4 basic amino acids are positively charged, that pro tons may be transferred among them, or to water and to acidic amino acids o n other segments in the channel. Finally, we consider the consequences of t he model for the distribution of the electrical potential at which the firs t step in gating begins; from this we obtain a reasonable relation between open probability and membrane potential, and an explanation of an experimen t (Fohlmeister and Adelman([1])) which has not hitherto been explained in a manner consonant with data available in 1998.