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Philip A. Gale - One of the best experts on this subject based on the ideXlab platform.
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tris thiourea tripodal based molecules as chloride Transmembrane Transporters insights from molecular dynamics simulations
Soft Matter, 2014Co-Authors: Igor Marques, Nathalie Busschaert, Philip A. Gale, Ana R Colaco, Paulo J Costa, Vitor FelixAbstract: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 ⊃ 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.
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structure activity relationships in tripodal Transmembrane anion Transporters the effect of fluorination
Journal of the American Chemical Society, 2011Co-Authors: Nathalie Busschaert, Mark E. Light, Marco Wenzel, Paulina Iglesiashernandez, Ricardo Pereztomas, Philip A. GaleAbstract:A series of easy-to-make fluorinated tripodal anion Transporters containing urea and thiourea groups have been prepared and their anion transport properties studied. Vesicle anion transport assays using ion-selective electrodes show that this class of compound is capable of transporting chloride through a lipid bilayer via a variety of mechanisms, including chloride/H+ cotransport and chloride/nitrate, chloride/bicarbonate, and to a lesser extent an unusual chloride/sulfate antiport process. Calculations indicate that increasing the degree of fluorination of the tripodal Transmembrane Transporters increases the lipophilicity of the transporter and this is shown to be the major contributing factor in the superior transport activity of the fluorinated compounds, with a maximum transport rate achieved for clog P = 8. The most active transporter 5 contained a urea functionality appended with a 3,5-bis(trifluoromethyl)phenyl group and was able to mediate Transmembrane chloride transport at receptor to lipid ra...
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thiourea isosteres as anion receptors and Transmembrane Transporters
Chemical Communications, 2011Co-Authors: Marco Wenzel, Anthony P Davis, Mark E. Light, Philip A. GaleAbstract:Compounds containing cyanoguanidine and 3-amino-1,2,4-benzothiadiazine-1,1-dioxide have been studied as anion receptors and Transporters. Significant affinity for oxo-anions was observed in organic solution and the receptors were found to function as Transmembrane chloride/nitrate antiporters with transport rates enhanced in the presence of valinomycin–K+ complex.
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Tripodal Transmembrane Transporters for bicarbonate
Chemical Communications, 2010Co-Authors: Nathalie Busschaert, Philip A. Gale, Cally J. E. Haynes, Mark E. Light, Stephen J. Moore, Christine C. Tong, Jeffery T. Davis, William A. HarrellAbstract:Easy-to-make tripodal tris-thiourea receptors based upon tris(2-aminoethyl)amine are capable of chloride/bicarbonate transport and as such represent a new class of bicarbonate transport agent.
Nathalie Busschaert - One of the best experts on this subject based on the ideXlab platform.
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tris thiourea tripodal based molecules as chloride Transmembrane Transporters insights from molecular dynamics simulations
Soft Matter, 2014Co-Authors: Igor Marques, Nathalie Busschaert, Philip A. Gale, Ana R Colaco, Paulo J Costa, Vitor FelixAbstract: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 ⊃ 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.
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structure activity relationships in tripodal Transmembrane anion Transporters the effect of fluorination
Journal of the American Chemical Society, 2011Co-Authors: Nathalie Busschaert, Mark E. Light, Marco Wenzel, Paulina Iglesiashernandez, Ricardo Pereztomas, Philip A. GaleAbstract:A series of easy-to-make fluorinated tripodal anion Transporters containing urea and thiourea groups have been prepared and their anion transport properties studied. Vesicle anion transport assays using ion-selective electrodes show that this class of compound is capable of transporting chloride through a lipid bilayer via a variety of mechanisms, including chloride/H+ cotransport and chloride/nitrate, chloride/bicarbonate, and to a lesser extent an unusual chloride/sulfate antiport process. Calculations indicate that increasing the degree of fluorination of the tripodal Transmembrane Transporters increases the lipophilicity of the transporter and this is shown to be the major contributing factor in the superior transport activity of the fluorinated compounds, with a maximum transport rate achieved for clog P = 8. The most active transporter 5 contained a urea functionality appended with a 3,5-bis(trifluoromethyl)phenyl group and was able to mediate Transmembrane chloride transport at receptor to lipid ra...
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Tripodal Transmembrane Transporters for bicarbonate
Chemical Communications, 2010Co-Authors: Nathalie Busschaert, Philip A. Gale, Cally J. E. Haynes, Mark E. Light, Stephen J. Moore, Christine C. Tong, Jeffery T. Davis, William A. HarrellAbstract:Easy-to-make tripodal tris-thiourea receptors based upon tris(2-aminoethyl)amine are capable of chloride/bicarbonate transport and as such represent a new class of bicarbonate transport agent.
Mark E. Light - One of the best experts on this subject based on the ideXlab platform.
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structure activity relationships in tripodal Transmembrane anion Transporters the effect of fluorination
Journal of the American Chemical Society, 2011Co-Authors: Nathalie Busschaert, Mark E. Light, Marco Wenzel, Paulina Iglesiashernandez, Ricardo Pereztomas, Philip A. GaleAbstract:A series of easy-to-make fluorinated tripodal anion Transporters containing urea and thiourea groups have been prepared and their anion transport properties studied. Vesicle anion transport assays using ion-selective electrodes show that this class of compound is capable of transporting chloride through a lipid bilayer via a variety of mechanisms, including chloride/H+ cotransport and chloride/nitrate, chloride/bicarbonate, and to a lesser extent an unusual chloride/sulfate antiport process. Calculations indicate that increasing the degree of fluorination of the tripodal Transmembrane Transporters increases the lipophilicity of the transporter and this is shown to be the major contributing factor in the superior transport activity of the fluorinated compounds, with a maximum transport rate achieved for clog P = 8. The most active transporter 5 contained a urea functionality appended with a 3,5-bis(trifluoromethyl)phenyl group and was able to mediate Transmembrane chloride transport at receptor to lipid ra...
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thiourea isosteres as anion receptors and Transmembrane Transporters
Chemical Communications, 2011Co-Authors: Marco Wenzel, Anthony P Davis, Mark E. Light, Philip A. GaleAbstract:Compounds containing cyanoguanidine and 3-amino-1,2,4-benzothiadiazine-1,1-dioxide have been studied as anion receptors and Transporters. Significant affinity for oxo-anions was observed in organic solution and the receptors were found to function as Transmembrane chloride/nitrate antiporters with transport rates enhanced in the presence of valinomycin–K+ complex.
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Tripodal Transmembrane Transporters for bicarbonate
Chemical Communications, 2010Co-Authors: Nathalie Busschaert, Philip A. Gale, Cally J. E. Haynes, Mark E. Light, Stephen J. Moore, Christine C. Tong, Jeffery T. Davis, William A. HarrellAbstract:Easy-to-make tripodal tris-thiourea receptors based upon tris(2-aminoethyl)amine are capable of chloride/bicarbonate transport and as such represent a new class of bicarbonate transport agent.
Vitor Felix - One of the best experts on this subject based on the ideXlab platform.
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tris thiourea tripodal based molecules as chloride Transmembrane Transporters insights from molecular dynamics simulations
Soft Matter, 2014Co-Authors: Igor Marques, Nathalie Busschaert, Philip A. Gale, Ana R Colaco, Paulo J Costa, Vitor FelixAbstract: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 ⊃ 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.
Austin L Hughes - One of the best experts on this subject based on the ideXlab platform.
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evolution of the atp binding cassette Transmembrane Transporters of vertebrates
Molecular Biology and Evolution, 1994Co-Authors: Austin L HughesAbstract:The ATP-binding-cassette Transmembrane Transporters (ABC Transporters) known from vertebrates belong to four major subfamilies: (1) the P-glycoproteins (Pgp); (2) the cystic fibrosis Transmembrane conductance regulators (CFTR); (3) the Tap proteins encoded with the major histocompatibility complex of mammals; and (4) the peroxisomal membrane proteins. Both Pgp and CFTR have a structure suggesting a past internal gene duplication; a phylogenetic analysis indicated that these duplications occurred independently, while an independent tandem gene duplication occurred in the case of the Tap family. Both the Pgp and Tap proteins show evidence of relationship to bacterial ABC Transporters lacking internal duplication, and both are significantly more closely related to the HlyB and MsbA families of Transporters from purple bacteria than they are to ABC Transporters from nonpurple bacteria. The simplest hypothesis to explain this observation is that eukaryotic Pgp and Tap genes are descended from a mitochondrial gene or genes that were subsequently translocated to the nuclear genome. The Pgp genes of eukaryotes are characterized by a remarkable degree of convergent evolution between the ATP-binding cassettes of their N-terminal and C-terminal halves, whereas no such convergence is seen between the two halves of CFTR genes or between the duplicated Tap genes. Exon 13 of the CFTR gene, which encodes a putative regulatory domain not found in other ABC Transporters apart from CFTR, showed high levels of both synonymous and nonsynonymous difference in comparisons among different mammalian species, suggesting that this region is a mutational hot spot.