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Issue 7, 2019
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Fluorinated synthetic anion carriers: experimental and computational insights into transmembrane chloride transport

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Abstract

A series of fluorinated tripodal tris-thioureas function as highly active anion transporters across lipid bilayers and cell membranes. Here, we investigate their mechanism of action using anion transport assays in cells and synthetic vesicles and molecular modelling of transporter–lipid interactions. When compared with non-fluorinated analogues, fluorinated compounds demonstrate a different mechanism of membrane transport because the free transporter cannot effectively diffuse through the membrane. As a result, in H+/Cl cotransport assays, fluorinated transporters require the presence of oleic acid to form anionic oleate complexes for recycling of the transporter, whereas non-fluorinated analogues readily diffuse through the membrane as free transporters and show synergistic transport with the proton transporter gramicidin. Molecular dynamics simulations revealed markedly stronger transporter–lipid interactions for fluorinated compounds compared with non-fluorinated analogues and hence, higher energy barriers for fluorinated compounds to cross the membrane as free transporters. With use of appropriate proton transporters to ensure measurement of the correct rate-limiting steps, the transport rates determined in synthetic vesicle assays show excellent agreement with the anion transport rates determined in cell-based assays. We conclude that integration of computational and experimental methods provides a strategy to optimise transmembrane anion transporter design for biomedical applications.

Graphical abstract: Fluorinated synthetic anion carriers: experimental and computational insights into transmembrane chloride transport

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Publication details

The article was received on 19 Nov 2018, accepted on 05 Dec 2018 and first published on 14 Dec 2018


Article type: Edge Article
DOI: 10.1039/C8SC05155K
Chem. Sci., 2019,10, 1976-1985
  • Open access: Creative Commons BY license
    All publication charges for this article have been paid for by the Royal Society of Chemistry

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    Fluorinated synthetic anion carriers: experimental and computational insights into transmembrane chloride transport

    M. J. Spooner, H. Li, I. Marques, P. M. R. Costa, X. Wu, E. N. W. Howe, N. Busschaert, S. J. Moore, M. E. Light, D. N. Sheppard, V. Félix and P. A. Gale, Chem. Sci., 2019, 10, 1976
    DOI: 10.1039/C8SC05155K

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