Tilting and Tumbling in Transmembrane Anion Carriers: Activity Tuning through n-Alkyl Substitution

authors	Edwards, SJ; Marques, I; Dias, CM; Tromans, RA; Lees, NR; Felix, V; Valkenier, H; Davis, AP
nationality	International
journal	CHEMISTRY-A EUROPEAN JOURNAL
author keywords	anion transport; lipophilicity; membranes; molecular dynamics; supramolecular chemistry
keywords	MOLECULAR-DYNAMICS SIMULATIONS; CHLORIDE TRANSPORT; FORCE-FIELD; RECEPTORS; AMBER; LIPOPHILICITY; ANIONOPHORES; EXTRACTION; PRINCIPLE; MEMBRANES
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 C-0 to C-10 in two-carbon steps. Activities increase then decrease as the chain length grows, peaking quite sharply at C-6. 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.
publisher	WILEY-V C H VERLAG GMBH
issn	0947-6539
year published	2016
volume	22
issue	6
beginning page	2004
ending page	2011
digital object identifier (doi)	10.1002/chem.201504057
web of science category	Chemistry, Multidisciplinary
subject category	Chemistry
unique article identifier	WOS:000368925200018