title: Length-Dependent Formation of Transmembrane Pores by 310-Helical α-Aminoisobutyric Acid Foldamers.
abstract: The synthetic biology toolbox lacks extendable and conformationally controllable yet easy-to-synthesize building blocks that are long enough to span membranes. To meet this need, an iterative synthesis of α-aminoisobutyric acid (Aib) oligomers was used to create a library of homologous rigid-rod 310-helical foldamers, which have incrementally increasing lengths and functionalizable N- and C-termini. This library was used to probe the inter-relationship of foldamer length, self-association strength, and ionophoric ability, which is poorly understood. Although foldamer self-association in nonpolar chloroform increased with length, with a ∼ 14-fold increase in dimerization constant from Aib6 to Aib11, ionophoric activity in bilayers showed a stronger length dependence, with the observed rate constant for Aib11 ∼ 70-fold greater than that of Aib6. The strongest ionophoric activity was observed for foldamers with >10 Aib residues, which have end-to-end distances greater than the hydrophobic width of the bilayers used (∼ 2.8 nm); X-ray crystallography showed that Aib11 is 2.93 nm long. These studies suggest that being long enough to span the membrane is more important for good ionophoric activity than strong self-association in the bilayer. Planar bilayer conductance measurements showed that Aib11 and Aib13, but not Aib7, could form pores. This pore-forming behavior is strong evidence that Aibm (m ≥ 10) building blocks can span bilayers.
authors.affiliation: School of Chemistry, University of Manchester , Oxford Road, Manchester M13 9PL, United Kingdom.|Manchester Institute of Biotechnology, University of Manchester , 131 Princess St, Manchester M1 7DN, United Kingdom.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Jones
authors.affiliation: School of Chemistry, University of Manchester , Oxford Road, Manchester M13 9PL, United Kingdom.|Manchester Institute of Biotechnology, University of Manchester , 131 Princess St, Manchester M1 7DN, United Kingdom.
authors.forename: Vincent
authors.initials: V
authors.lastname: Diemer
authors.affiliation: School of Chemistry, University of Manchester , Oxford Road, Manchester M13 9PL, United Kingdom.|School of Chemistry, University of Bristol , Cantock's Close, Bristol BS8 1TS, United Kingdom.
authors.forename: Catherine
authors.initials: C
authors.lastname: Adam
authors.affiliation: School of Chemistry, University of Manchester , Oxford Road, Manchester M13 9PL, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Raftery
authors.affiliation: School of Chemistry, University of Manchester , Oxford Road, Manchester M13 9PL, United Kingdom.
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Ruscoe
authors.affiliation: Department of Chemistry, University of Oxford , 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Sengel
authors.affiliation: Department of Chemistry, University of Oxford , 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
authors.forename: Mark I
authors.initials: MI
authors.lastname: Wallace
authors.affiliation: EaStCHEM School of Chemistry, University of Edinburgh , Joseph Black Building, David Brewster Road, Edinburgh EH9 3FJ, United Kingdom.
authors.forename: Antoine
authors.initials: A
authors.lastname: Bader
authors.affiliation: EaStCHEM School of Chemistry, University of Edinburgh , Joseph Black Building, David Brewster Road, Edinburgh EH9 3FJ, United Kingdom.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Cockroft
authors.affiliation: School of Chemistry, University of Manchester , Oxford Road, Manchester M13 9PL, United Kingdom.|School of Chemistry, University of Bristol , Cantock's Close, Bristol BS8 1TS, United Kingdom.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Clayden
authors.affiliation: School of Chemistry, University of Manchester , Oxford Road, Manchester M13 9PL, United Kingdom.|Manchester Institute of Biotechnology, University of Manchester , 131 Princess St, Manchester M1 7DN, United Kingdom.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Webb
mesh_terms: D000621:Aminoisobutyric Acids / Q000737:chemistry*; D002462:Cell Membrane; D018360:Crystallography, X-Ray; D005453:Fluorescence; D015394:Molecular Structure
chemical_list: D000621:Aminoisobutyric Acids; C100049:2-aminoisobutyric acid