Tris-thiourea tripodal-based molecules as chloride transmembrane transporters: insights from molecular dynamics simulations
authors Marques, I; Colaco, AR; Costa, PJ; Busschaert, N; Gale, PA; Felix, V
nationality International
journal SOFT MATTER
keywords AMBER FORCE-FIELD; SYNTHETIC MEMBRANE TRANSPORTERS; ANION RECEPTOR CHEMISTRY; BIOMOLECULAR SIMULATIONS; LIPID-BILAYERS; HIGHLIGHTS; CHANNELOPATHIES; VALIDATION; CHANNEL; MODEL
abstract The interaction of six tripodal synthetic chloride transmembrane transporters with a POPC bilayer was investigated by means of molecular dynamics simulations using the general Amber force field (GAFF) for the transporters and the LIPID11 force field for phospholipids. These transporters are structurally simple molecules, based on the tris(2-aminoethyl) amine scaffold, containing three thiourea binding units coupled with three n-butyl (1), phenyl (2), fluorophenyl (3), pentafluorophenyl (4), trifluoromethylphenyl (5), or bis(trifluoromethyl) phenyl (6) substituents. The passive diffusion of 1-6 superset of Cl- was evaluated with the complexes initially positioned either in the water phase or inside the bilayer. In the first scenario the chloride is released in the water solution before the synthetic molecules achieve the water-lipid interface and permeate the membrane. In the latter one, only when the chloride complex reaches the interface is the anion released to the water phase, with the transporter losing the initial ggg tripodal shape. Independently of the transporter used in the membrane system, the bilayer structure is preserved and the synthetic molecules interact with the POPC molecules at the phosphate headgroup level, via N-H...O hydrogen bonds. Overall, the molecular dynamics simulations' results indicate that the small tripodal molecules in this series have a low impact on the bilayer and are able to diffuse with chloride inside the lipid environment. Indeed, these are essential conditions for these molecules to promote the transmembrane transport as anion carriers, in agreement with experimental efflux data.
publisher ROYAL SOC CHEMISTRY
issn 1744-683X
year published 2014
volume 10
issue 20
beginning page 3608
ending page 3621
digital object identifier (doi) 10.1039/c3sm52140k
web of science category Chemistry, Physical; Materials Science, Multidisciplinary; Physics, Multidisciplinary; Polymer Science
subject category Chemistry; Materials Science; Physics; Polymer Science
unique article identifier WOS:000335927400010
link 24663079

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