Synthesis and AFM-based Single-Molecule Force Spectroscopy of Helical Aromatic Oligoamide foldamers

In this work, we describe the synthesis of aromatic oligoamide foldamers designed for AFM-based single-molecule force spectroscopy (SMFS) and the detailed investigation of their mechanical properties by this technique. The aim of the thesis was to gain insights into the forces governing the folding and the mechanochemical properties of synthetic folded molecules.
We designed and studied three different kinds of helical foldamers to investigate the influence of the size of the foldamer and of the chemical architecture on the mechanical properties at the level of the single molecule in organic solvents. Pulling experiments on quinoline-based foldamers of four different sizes revealed a characteristic unfolding pattern, consistent with the sequential opening of the same groups of interactions involved in the helical conformation. The length of the unfolding patterns is proportional to the foldamer size, while the average unfolding forces show non-linear force dependence. This result highlighted the cooperativity of the interactions originating from the chemical sequence in the folding. From pulling-relaxing SMFS experiments, we evaluated the unfolding free energies and evidenced the capacity of the unfolded molecules to rapidly refold under the mechanical load. Together with experiments in different solvents, these results demonstrate the high robustness of this class of foldamers. SMFS experiments on the naphthyridine-constituted foldamer confirmed its helical structure and suggested that the strength of the interactions along the foldamer are weaker for a wider helix. The insertion of a methylene bridge in the aromatic oligoamide sequence showed a substantial effect on the mechanical properties. The aliphatic junction indeed disrupts the interaction continuum in the helical conformation under load.
Providing detailed characterizations down to the single-molecule level, which are complementary to the traditional ensemble experiments, we also showed that helically folded aromatic oligoamides are a genuine class of foldamers with very promising properties as building blocks for mechanized nanomachines.