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

Full elucidation of the transmembrane anion transport mechanism of squaramides using: In silico investigations
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 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.

1463-9076
20796-20811
Marques, Igor
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Costa, Pedro M.R.
a956ddb9-002e-4c69-aa85-c0dafe913cdb
Miranda, Margarida Q.
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Busschaert, Nathalie
9abe79c0-7540-4677-bf27-84e8e0e048f6
Howe, Ethan N.W.
be05ae9a-02e0-443b-97b2-d65cc387af40
Clarke, Harriet J.
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Haynes, Cally J.E.
54c30472-2ae9-402c-a588-425443df54aa
Kirby, Isabelle L.
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Rodilla, Ananda M.
cd777bcd-c3bf-473a-887f-be599eed9e29
Pérez-Tomás, Ricardo
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Gale, Philip A.
c840b7e9-6847-4843-91af-fa0f8563d943
Félix, Vítor
b4098ac2-b86b-48f3-af11-c767e24fac6e
Marques, Igor
97cbc26e-6d94-43e6-a934-1d69dad8de06
Costa, Pedro M.R.
a956ddb9-002e-4c69-aa85-c0dafe913cdb
Miranda, Margarida Q.
f4ae5b90-cc88-40da-9e53-a5742fa745f6
Busschaert, Nathalie
9abe79c0-7540-4677-bf27-84e8e0e048f6
Howe, Ethan N.W.
be05ae9a-02e0-443b-97b2-d65cc387af40
Clarke, Harriet J.
f5c240ce-625a-47b4-a835-8b7cb44681d2
Haynes, Cally J.E.
54c30472-2ae9-402c-a588-425443df54aa
Kirby, Isabelle L.
4c9f03c1-1c0a-48ab-a2ae-6558c6904ac7
Rodilla, Ananda M.
cd777bcd-c3bf-473a-887f-be599eed9e29
Pérez-Tomás, Ricardo
65d20fa5-9cc1-4a21-b7f9-56a6ec287eb7
Gale, Philip A.
c840b7e9-6847-4843-91af-fa0f8563d943
Félix, Vítor
b4098ac2-b86b-48f3-af11-c767e24fac6e

Marques, Igor, Costa, Pedro M.R., Miranda, Margarida Q., 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. and Félix, Vítor (2018) Full elucidation of the transmembrane anion transport mechanism of squaramides using: In silico investigations. Physical Chemistry Chemical Physics, 20 (32), 20796-20811. (doi:10.1039/c8cp02576b).

Record type: Article

Abstract

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.

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Accepted/In Press date: 29 June 2018
e-pub ahead of print date: 3 July 2018
Published date: 2018

Identifiers

Local EPrints ID: 424428
URI: http://eprints.soton.ac.uk/id/eprint/424428
ISSN: 1463-9076
PURE UUID: 2f15bf22-afaa-4963-a7a4-c37a3f615c50
ORCID for Philip A. Gale: ORCID iD orcid.org/0000-0001-9751-4910

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Date deposited: 05 Oct 2018 11:37
Last modified: 20 Apr 2021 01:38

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