TCB Publications - Abstract

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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