Molecular basis of CLC antiporter inhibition by fluoride.

CLC channels and transporters conduct or transport various kinds of anions, with the ex-ception of fluoride that acts as an effective in-hibitor. Here, we performed sub-ns DFT-based QM/MM simulations of the E. coli anion/proton exchanger ClC-ec1 and observed that fluoride binds incoming protons within the selectivity filter, with excess protons shared with the gating glutamate E148. Depending on E148 confor-mation, the competition for the proton can in-volve either a direct F-/E148 interaction or the modulation of water molecules bridging the two anions. The direct interaction locks E148 in a conformation that does not allow for proton transport, and thus inhibits protein function.