Full elucidation of the transmembrane anion transport mechanism of squaramides using in silico investigations

A comprehensive experimental and theoretical investigation of the transmembrane chloride transport promoted by four series of squaramide derivatives, with different degrees of fluorination, number of convergent N-H binding units and conformational shapes, is reported. The experimental chloride bindi...

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Bibliographic Details
Published in:Physical chemistry chemical physics : PCCP 2018, Vol.20 (32), p.20796-20811
Main Authors: Marques, Igor, Costa, Pedro M R, Q Miranda, Margarida, Busschaert, Nathalie, Howe, Ethan N W, Clarke, Harriet J, Haynes, Cally J E, Kirby, Isabelle L, Rodilla, Ananda M, Pérez-Tomás, Ricardo, Gale, Philip A, Félix, Vítor
Format: Article
Language:English
Subjects:
Affinity
Anions
Anions - chemistry
Binding
Biological transport
Chloride
Chlorides
Clorurs
Computer Simulation
Diffusion
Fluorination
Hydrogen Bonding
Ion Transport
Liposomes
Liposomes - chemistry
Molecular Conformation
Molecular dynamics
Molecular Dynamics Simulation
Phospholipids
Phospholipids - chemistry
Quantum Theory
Quinine - analogs & derivatives
Quinine - chemistry
Química supramolecular
Supramolecular chemistry
Thermodynamics
Transport
Transport biològic
Water - chemistry
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Summary:A comprehensive experimental and theoretical investigation of the transmembrane chloride transport promoted by four series of squaramide derivatives, with different degrees of fluorination, number of convergent N-H binding units and conformational shapes, is reported. The experimental chloride binding and transport abilities of these small synthetic molecules in liposomes were rationalised with quantum descriptors and molecular dynamics simulations in POPC bilayers. The tripodal tren-based compounds, with three squaramide binding motifs, have high chloride affinity, isolating the anion from water molecules within the membrane model and preventing its release to the aqueous phase, in agreement with the absence of experimental transport activity. In contrast, the symmetrical mono-squaramides, with moderate chloride binding affinity, are able to bind and release chloride either in the aqueous phase or at the membrane interface level, in line with experimentally observed high transport activity. The PMF profiles associated with the diffusion of these free transporters and their chloride complexes across phospholipid bilayers show that the assisted chloride translocation is thermodynamically favoured.
ISSN:1463-9076
1463-9084
DOI:10.1039/c8cp02576b