Length-Dependent Formation of Transmembrane Pores by 310-Helical α-Aminoisobutyric Acid Foldamers

Jennifer E Jones, Vincent Diemer, Catherine Adam, James Raftery, Rebecca E Ruscoe, Jason T Sengel, Mark I Wallace, Antoine Bader, Scott L Cockroft, Jonathan Clayden*, Simon J Webb

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

41 Citations (Scopus)
312 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)688-695
Number of pages8
JournalJournal of the American Chemical Society
Volume138
Issue number2
Early online date23 Dec 2015
DOIs
Publication statusPublished - 20 Jan 2016

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