title: Tilting and Tumbling in Transmembrane Anion Carriers: Activity Tuning through n-Alkyl Substitution.
abstract: Anion transport by synthetic carriers (anionophores) holds promise for medical applications, especially the treatment of cystic fibrosis. Among the factors which determine carrier activity, the size and disposition of alkyl groups is proving remarkably important. Herein we describe a series of dithioureidodecalin anionophores, in which alkyl substituents on one face are varied from C0to C10in two-carbon steps. Activities increase then decrease as the chain length grows, peaking quite sharply at C6. Molecular dynamics simulations showed the transporter chloride complexes releasing chloride as they approach the membrane-aqueous interface. The free transporter then stays at the interface, adopting an orientation that depends on the alkyl substituent. If chloride release is prevented, the complex is positioned similarly. Longer chains tilt the binding site away from the interface, potentially freeing the transporter or complex to move through the membrane. However, chains which are too long can also slow transport by inhibiting movement, and especially reorientation, within the phospholipid bilayer.
authors.affiliation: School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, UK.
authors.forename: Sophie J
authors.initials: SJ
authors.lastname: Edwards
authors.affiliation: Departamento de Química, iBiMED and CICECO, Universidade de Aveiro, 3810-193, Aveiro, Portugal.
authors.forename: Igor
authors.initials: I
authors.lastname: Marques
authors.affiliation: School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dias
authors.affiliation: School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, UK.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Tromans
authors.affiliation: School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, UK.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Lees
authors.affiliation: Departamento de Química, iBiMED and CICECO, Universidade de Aveiro, 3810-193, Aveiro, Portugal. Vitor.Felix@ua.pt.
authors.forename: Vítor
authors.initials: V
authors.lastname: Félix
authors.affiliation: School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, UK. Hennie.Valkenier@bristol.ac.uk.
authors.forename: Hennie
authors.initials: H
authors.lastname: Valkenier
authors.affiliation: School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, UK. Anthony.Davis@bristol.ac.uk.
authors.forename: Anthony P
authors.identifier: http://orcid.org/0000-0001-5213-624X
authors.initials: AP
authors.lastname: Davis
keywords: anion transport; lipophilicity; membranes; molecular dynamics; supramolecular chemistry