Issue 7, 2019

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

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

Supplementary files

Article information

Article type
Edge Article
Submitted
19 nov 2018
Accepted
05 dec 2018
First published
14 dec 2018
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2019,10, 1976-1985

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

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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