Abstract
CLC 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. The direct interaction locks E148 in a conformation that does not allow for proton transport, and thus inhibits protein function.
| Original language | English |
|---|---|
| Pages (from-to) | 7254-7258 |
| Number of pages | 5 |
| Journal | Journal of the American Chemical Society |
| Volume | 142 |
| Issue number | 16 |
| DOIs | |
| State | Published - Apr 22 2020 |
| Externally published | Yes |
Funding
The authors gratefully acknowledge the computing time granted through JARA-HPC on the supercomputer JURECA at Forschungszentrum Jülich (Project ID: jias5f). J.M.H.O. acknowledges financial support from the Research Council of Norway through its Centers of Excellence scheme (Project ID: 262695). T.L.B. acknowledges the support of the U.S. National Science Foundation grants CHE-15656632 and CHE-1955161 for partial support of this research. M.G.C., C.F., and P.C. acknowledge the funding by the Deutsche Forschungsgemeinschaft via FOR 2518 DynIon project P6. P.C. thanks the support of BioExcel ( www.bioexel.eu ), a project funded by the European Union contracts H2020-INFRAEDI-02-2018-823830 and H2020-EINFRA-2015-1-675728. The authors gratefully acknowledge the computing time granted through JARA-HPC on the supercomputer JURECA at Forschungszentrum JuÌlich (Project ID: jias5f). J.M.H.O. acknowledges financial support from the Research Council of Norway through its Centers of Excellence scheme (Project ID: 262695). T.L.B. acknowledges the support of the U.S. National Science Foundation grants CHE-15656632 and CHE-1955161 for partial support of this research. M.G.C., C.F., and P.C. acknowledge the funding by the Deutsche Forschungsgemeinschaft via FOR 2518 DynIon project P6. P.C. thanks the support of BioExcel (www.bioexel.eu), a project funded by the European Union contracts H2020-INFRAEDI-02-2018-823830 and H2020-EINFRA-2015-1-675728.