000884077 001__ 884077 000884077 005__ 20230522110535.0 000884077 0247_ $$2doi$$a10.1021/jacs.9b13588 000884077 0247_ $$2ISSN$$a0002-7863 000884077 0247_ $$2ISSN$$a1520-5126 000884077 0247_ $$2ISSN$$a1943-2984 000884077 0247_ $$2Handle$$a2128/25668 000884077 0247_ $$2altmetric$$aaltmetric:78970360 000884077 0247_ $$2pmid$$apmid:32233472 000884077 0247_ $$2WOS$$aWOS:000529156100003 000884077 037__ $$aFZJ-2020-03078 000884077 082__ $$a540 000884077 1001_ $$00000-0003-1076-682X$$aChiariello, Maria Gabriella$$b0$$eCorresponding author 000884077 245__ $$aMolecular Basis of CLC Antiporter Inhibition by Fluoride 000884077 260__ $$aWashington, DC$$bAmerican Chemical Society$$c2020 000884077 3367_ $$2DRIVER$$aarticle 000884077 3367_ $$2DataCite$$aOutput Types/Journal article 000884077 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1603697344_28681 000884077 3367_ $$2BibTeX$$aARTICLE 000884077 3367_ $$2ORCID$$aJOURNAL_ARTICLE 000884077 3367_ $$00$$2EndNote$$aJournal Article 000884077 520__ $$aCLC channels and transporters conduct or transport various kinds of anions, with the exception of fluoride, which acts as an effective inhibitor. Here, we performed sub-nanosecond 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 conformation, the competition for the proton can involve either a direct F–/E148 interaction or the modulation of water molecules bridging the two anions. 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