Jordi Cohen and Klaus Schulten.
Mechanism of anionic conduction across CLC.
Biophysical Journal, 86:836-845, 2004.
(PMC: 1303931)
COHE2004
ClC chloride channels are voltage-gated transmembrane proteins which
have been associated with a wide range of regulatory roles in
vertebrates. To accomplish their function, they furnish efficient passage
of small inorganic anions to the exclusion of all other particles.
Understanding ClC's conduction mechanism has been the subject of
intense experimental characterizations, but until now the detailed
dynamic mechanism was not known despite the availability of
crystallographic structures. We investigate conduction by means of
an all-atom molecular dynamics simulation of the ClC channel in a
membrane environment. The simulations reveal a ``king of the hill"
mechanism for permeation, in which a lone ion bound to the center of a
pore is pushed out by a second ion which enters the pore and takes its
place. While the energy required to extract the single central ion from
the pore is enormous, by resorting to this two-ion process, the largest
free energy barrier for conduction is reduced to 4 kcal/mol. At the
narrowest part of the pore, residues Tyr 445 and Ser 107
stabilize the central ion. There, the bound ion blocks the pore,
disrupting the formation of a continuous water file that could leak
protons and preventing the passage of uncharged solutes.
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