Ion channel gating and proton transport

Abstract

A model of ion channel gating has been proposed (J. Biomol. Struct. Dyn. 19 (2002) 725). It includes the following. (1) There is a bacterial channel for which an X-ray structure is known (KcsA) that opens (‘gates’) with a drop in pH. In the proposal, a proton gates this channel by adding a charge to the glutamate residues that form the center of the gating region. It is postulated that two water molecules form a strong short hydrogen bond when the glutamates plus the water have a −2 charge. Adding a proton leads to a normal, weak, hydrogen bond, and the groups can separate, opening the channel. gaussian 98 calculations support this part of the proposal (J. Phys. Chem. B 105 (2001) 5298). (2) Voltage gated channels contain six transmembrane (TM) segments in each of four domains. We suggest that the additional four TM segments (KcsA has two) act as a voltage-to-proton current transducer. In the model, the first step in gating is proton tunneling (J. Phys. Chem. A 102 (1998) 7181), followed by a proton cascade. Calculations supporting the latter step are presented here. One of the eukaryotic TM segments, S4, is known to be involved in gating. This segment has arginines (occasionally lysine) at every third amino acid. The arginines appear capable of transmitting a proton, or possibly a proton cascade (three per S4 would produce the observed charge movement (‘gating current’) that precedes gating). We have carried out density functional calculations, using gaussian 98, on a system that includes: one pair of guanidinium groups, the side chains of arginines responsible for carrying the proton current; a mobile proton; one, two or three water molecules. Several guanidinium spacings have been tried, all in the range of carbon–carbon distances 4–6 Å. The potential energy surface was computed for each, and a minimum path found for the proton, at B3LYP/6-311G** level. It was found that the proton, under some conditions, could follow a path between guanidiniums that had no barriers greater than a few kT (thermal energy), thereby supporting the proposal that protons could move along the chain of guanidiniums.