Towards Understanding the Mechanical Properties of Protein Secondary Structures: A Single-Molecule Force Spectroscopy Study of Synthetic Helical Foldamers

For thousands of years, nature has selected and perfected the conformation foldings of its molecular machines. They are set out to fulfill the most diverse chemical or mechanical functions in nature. In order to understand reaction pathways of such bio-molecular machines and to mimic nature’s creations using chemical syntheses, it is essential to understand the origins of molecular foldings and their influence on the mechanical properties of these machines. We specifically designed synthetic molecular models of secondary helical structures to allow us to simplify the many parameters occurring simultaneously in nature. The aim of our study is two-fold: identify the relationships between the chemical sequence of the foldamers and their (un)folding forces and mechanisms and expand the limits of Single-Molecule Force Spectroscopy (SMFS) as our model systems are much smaller than natural (bio)polymers. Here, we study the mechanochemical properties of our folded aromatic oligoamides [Huc, 2014] at the monomolecular level using SMFS with an Atomic Force Microscope. We investigated several different sizes of foldamers in solution. Each of the foldamers yielded reproducible and specific force-extension curves, showing a characteristic unfolding pattern with multiple features. The unfolding pattern was consistent with a sequential opening of entities with identical interactions. While the measured pattern lengths were directly proportional to the foldamer sizes, the average unfolding forces showed a non-linear dependence on the foldamer size. This could be retraced to cooperative effects in the foldamer sequence. Finally, compared to natural biopolymers [Ritort, 2016;, Seitz, 2001], our foldamers exhibited increased stabilities when submitted to external loads. The interactions at the origin of this observation were selectively investigated by performing a solvent study