Interplay of secondary and tertiary folding in abiotic foldamers

Abstract

The first true abiotic tertiary folded structures, i.e. at the exclusion of any aliphatic amino acid, have recently been introduced under the form of aromatic oligoamide helix–turn–helix foldamers stabilized by hydrogen bonds in organic solvents. We present an investigation of the interplay of secondary and tertiary folding and of some cooperative effects in these systems. A solid phase synthesis approach to the preparation of these sequences was developed to facilitate systematic variation. Flexible pyridine-based units were introduced in various proportions in replacement of more rigid quinoline-based units. Conformational behaviour was assessed in solution by NMR, in the solid state by X-ray crystallography, and computationally through molecular dynamics simulations. Altogether, our results demonstrate that tertiary folding stabilizes otherwise flexible secondary structures, and that the disruption of tertiary folds upon adding polar solvents follows different mechanisms depending on whether secondary structures are inherently stable or not. These findings constitute a solid basis on which to further increase the size and complexity of abiotic folded structures and to eventually orchestrate folding dynamics and responsiveness.