Length-Dependent Formation of Transmembrane Pores by 310-Helical ?-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 ?-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.

SUBMITTER: Jones JE 

PROVIDER: S-EPMC4752191 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature