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The ClC family of transmembrane proteins functions throughout nature to control the transport of Cl - ions across biological membranes. ClC-ec1 from Escherichia coli is an antiporter, coupling the transport of Cl - and H + ions in opposite directions and driven by the concentration gradients of the ions. Despite keen interest in this protein, the molecular mechanism of the Cl - /H + coupling has not been fully elucidated. Here, we have used multiscale simulation to help identify the essential mechanism of the Cl - /H + coupling. We find that the highest barrier for proton transport (PT) from the intra- to extracellular solution is attributable to a chemical reaction, the deprotonation of glutamic acid 148 (E148). This barrier is significantly reduced by the binding of Cl - in the "central" site (Cl -  cen ), which displaces E148 and thereby facilitates its deprotonation. Conversely, in the absence of Cl -  cen E148 favors the "down" conformation, which results in a much higher cumulative rotation and deprotonation barrier that effectively blocks PT to the extracellular solution. Thus, the rotation of E148 plays a critical role in defining the Cl - /H + coupling. As a control, we have also simulated PT in the ClC-ec1 E148A mutant to further understand the role of this residue. Replacement with a non-protonatable residue greatly increases the free energy barrier for PT from E203 to the extracellular solution, explaining the experimental result that PT in E148A is blocked whether or not Cl -  cen is present. The results presented here suggest both how a chemical reaction can control the rate of PT and also how it can provide a mechanism for a coupling of the two ion transport processes.

The Origin of Coupled Chloride and Proton Transport in a Cl–/H+ Antiporter

The Origin of Coupled Chloride and Proton Transport in a Cl^–/H⁺ Antiporter