In recent years, we have developed a computational approach that allows accurate prediction of secondary structures and solution dynamics of arylamide foldamers. In this presentation, we focus on the applications of this approach in investigating folding/unfolding pathways of helical arylamides. Our metadynamics study of quinoline oligoamides provides the first atomistic level description of the mechanism for handedness inversion of helical arylamide foldamers. The key process in the inversion is simultaneous unfolding and folding of two adjacent aryl-aryl linkages, propagating from a helix terminus along the strand. Intermediates along the inversion pathway have a common feature - a single unfolded aryl-aryl linkage (through C<sub>aryl</sub>-C<sub>amide </sub>rotation) connecting two helical segments of opposite handedness. The free energy profiles obtained are in agreement with experimentally obtained kinetic data. Furthermore, we have studied the mechanism of handedness induction in quinoline oligoamides, caused by attaching a chiral group at either the C- or N-terminus. Using the experimentally verified chiral induction groups and the metadynamics approach, we obtained free energy profiles of the inversion and show that the preferred helix handedness can be accurately predicted by computational means. In addition, analysis of conformers with opposite handedness reveals structural and energetics differences between the preferred and non-favoured handed helices. Our studies provide vital insight into the folding process of arylamide helices, which can inform and facilitate the rational design of functional foldamers.

Helix handedness inversion and induction in arylamide foldamers: Elucidation and free energy profile of the folding/unfolding mechanism

251st National Meeting (2016)

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