Length-Dependent Formation of Transmembrane Pores by 3 10 -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

Research output: Contribution to journalArticlepeer-review

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
JournalJournal of the American Chemical Society
Volume138
Issue number2
DOIs
Publication statusPublished - 23 Dec 2015

Fingerprint

Dive into the research topics of 'Length-Dependent Formation of Transmembrane Pores by 3 10 -Helical α-Aminoisobutyric Acid Foldamers'. Together they form a unique fingerprint.

Cite this