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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<jats:sub>0<\/jats:sub> to C<jats:sub>10<\/jats:sub> in two\u2010carbon steps. Activities increase then decrease as the chain length grows, peaking quite sharply at C<jats:sub>6<\/jats:sub>. Molecular dynamics simulations showed the transporter chloride complexes releasing chloride as they approach the membrane\u2010aqueous 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.<\/jats:p>","DOI":"10.1002\/chem.201504057","type":"journal-article","created":{"date-parts":[[2016,1,10]],"date-time":"2016-01-10T09:05:49Z","timestamp":1452416749000},"page":"2004-2011","source":"Crossref","is-referenced-by-count":25,"title":["Tilting and Tumbling in Transmembrane Anion Carriers: Activity Tuning through <i>n<\/i>\u2010Alkyl Substitution"],"prefix":"10.1002","volume":"22","author":[{"given":"Sophie J.","family":"Edwards","sequence":"first","affiliation":[{"name":"School of Chemistry University of Bristol  Cantock's Close Bristol BS8 1TS UK"}]},{"given":"Igor","family":"Marques","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica iBiMED and CICECO Universidade de Aveiro  3810-193 Aveiro Portugal"}]},{"given":"Christopher M.","family":"Dias","sequence":"additional","affiliation":[{"name":"School of Chemistry University of Bristol  Cantock's Close Bristol BS8 1TS UK"}]},{"given":"Robert A.","family":"Tromans","sequence":"additional","affiliation":[{"name":"School of Chemistry University of Bristol  Cantock's Close Bristol BS8 1TS UK"}]},{"given":"Nicholas R.","family":"Lees","sequence":"additional","affiliation":[{"name":"School of Chemistry University of Bristol  Cantock's Close Bristol BS8 1TS UK"}]},{"given":"V\u00edtor","family":"F\u00e9lix","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica iBiMED and CICECO Universidade de Aveiro  3810-193 Aveiro Portugal"}]},{"given":"Hennie","family":"Valkenier","sequence":"additional","affiliation":[{"name":"School of Chemistry University of Bristol  Cantock's Close Bristol BS8 1TS UK"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5213-624X","authenticated-orcid":false,"given":"Anthony P.","family":"Davis","sequence":"additional","affiliation":[{"name":"School of Chemistry University of Bristol  Cantock's Close Bristol BS8 1TS UK"}]}],"member":"311","published-online":{"date-parts":[[2016,1,8]]},"reference":[{"key":"e_1_2_5_1_1","unstructured":"\u00a0"},{"key":"e_1_2_5_2_2","doi-asserted-by":"publisher","DOI":"10.1039\/B512651G"},{"key":"e_1_2_5_3_2","doi-asserted-by":"publisher","DOI":"10.1039\/b817245p"},{"key":"e_1_2_5_4_2","doi-asserted-by":"publisher","DOI":"10.1039\/b926164h"},{"key":"e_1_2_5_5_2","doi-asserted-by":"publisher","DOI":"10.1039\/c0cs00209g"},{"key":"e_1_2_5_6_2","doi-asserted-by":"publisher","DOI":"10.1021\/ar4000345"},{"key":"e_1_2_5_7_2","doi-asserted-by":"publisher","DOI":"10.1021\/ar400019p"},{"key":"e_1_2_5_8_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.5b00099"},{"key":"e_1_2_5_9_1","volume-title":"Ion Channels and Disease","author":"Ashcroft F. 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