Modeling the fast gating mechanism in the ClC-0 chloride channel

A simplified three-dimensional model ClC-0 chloride channel is constructed to couple the permeation of Cl- ions to the motion of a glutamate side chain that acts as the putative fast gate in the ClC-0 channel. The gate is treated as a single spherical particle attached by a rod to a pivot point. This particle moves in a one-dimensional arc under the influence of a bistable potential, which mimics the isomerization process by which the glutamate side chain moves from an open state (not blocking the channel pore) to a closed state (blocking the channel pore, at a position which also acts as a binding site for Cl- ions moving through the channel). A dynamic Monte Carlo (DMC) technique is utilized to perform Brownian dynamics simulations to investigate the dependence of the gate closing rate on both internal and external chloride concentration and the gate charge as well. To accelerate the simulation of gate closing to a time scale that can be accommodated with current methodology and computer power, namely, microseconds, parameters that govern the motion of the bare gate (i.e., in the absence of coupling to the permeating ions) are chosen appropriately. Our simulation results are in qualitative agreement with experimental observations and consistent with the "foot-in-the-door" mechanism (Chen et al. J. Gen. Physiol. 2003, 122, 641; Chen and Miller J. Gen. Physiol. 1996, 108, 237), although the absolute time scale of gate closing in the real channel is much longer (millisecond time scale). A simple model based on the fractional occupation probability of the Cl- binding site that is ultimately blocked by the fast gate suggests straightforward scalability of simulation results for the model channel considered herein to experimentally realistic time scales.