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

Research output: Contribution to journalArticle

  • External authors:
  • Jennifer Jones
  • Vincent Diemer
  • Catherine Adam
  • James Raftery
  • Rebecca Ruscoe
  • Jason Sengel
  • Mark Wallace
  • Antoine Bader
  • Scott L. Cockroft
  • Jonathan Clayden

Abstract

The synthetic biology toolbox lacks extendable andconformationally controllable yet easy-to-synthesize building blocksthat are long enough to span membranes. To meet this need, aniterative synthesis of α-aminoisobutyric acid (Aib) oligomers was used tocreate a library of homologous rigid-rod 310-helical foldamers, which haveincrementally 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 poorlyunderstood. Although foldamer self-association in nonpolar chloroformincreased with length, with a ∼14-fold increase in dimerization constantfrom Aib6 to Aib11, ionophoric activity in bilayers showed a strongerlength dependence, with the observed rate constant for Aib11 ∼70-foldgreater than that of Aib6. The strongest ionophoric activity was observedfor foldamers with >10 Aib residues, which have end-to-end distancesgreater 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 strongself-association in the bilayer. Planar bilayer conductance measurements showed that Aib11 and Aib13, but not Aib7, could formpores. This pore-forming behavior is strong evidence that Aibm (m ≥ 10) building blocks can span bilayers.

Bibliographical metadata

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