Transmembrane transporters play important roles in many essential biochemical cell processes across all kingdoms of life. Their (mal)function is related to many diseases or drug resistances. For instance, fluoride (F-) which is an abundant natural antibiotic is being exported by F- transporters from bacterial cells when its cellular concentration is at toxic levels. F- transporters belong to two broad families: 1) CLCF F-/H+ antiporters, exclusively found in eubacteria and 2) F- ion channels, found in bacteria and eukaryotes. Despite some studies on these F- transporters, there are still many questions unanswered in the field. The central questions are how F- transporters achieve a high F- selectivity over HF or Cl-, and whether we can control this ion selectivity. To address these questions, we used a variety of computational approaches to uncover details about their dynamics, structure, selectivity, and transport mechanism. We performed molecular dynamics (MD), umbrella sampling and computational electrophysiology simulations on these two proteins and identified important residues and key interactions for F- selectivity and export mechanism in each. Additionally, we showed the proton import is coupled with F- export in CLCF, in which proton is being transported through two glutamate residues. Further, we explained how these proteins achieved high selectivity for F- compared to HF. Our findings will pave the way for scientists to examine whether F- exporters could be used as novel targets for antibiotics.

Computational studies of novel microbial F- exporters

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