  ClC chloride channels possess a homodimeric structure in which each monomer
contains an independent chloride ion pathway. ClC channel gating is regulated
by chloride ion concentration, pH, and voltage. Based on structural and
physiological evidence, it has been proposed that a glutamate residue on the
extracellular end of the selectivity filter acts as a fast gate. We utilize a
new search algorithm which incorporates electrostatic information to explore
the ion transit pathways through wild-type and mutant bacterial ClC channels.
Examination of the chloride ion permeation pathways supports the proposed
important role of the glutamate residue in gating. An external chloride binding
site previously postulated in physiological experiments is located near a
conserved basic residue adjacent to the gate. In addition, access pathways are
found for proton migration to the gate, enabling pH control at hyperpolarized
membrane potentials. A chloride ion in the selectivity filter is required for
the pH-dependent gating mechanism.
