Solvent-Dependent Folding Behavior of a Helix-Forming Aryl-Triazole Foldamer

Aromatic foldamers make up a novel class of bioinspired molecules that display helical conformations and have functions that rely on control over their coil-helix folding preferences. While the folding has been extensively examined by experiment, it has rarely been paired with the types of atomic level insights offered by theory. We present the results of all-atom molecular dynamics (MD) simulations to examine the role of solvent polarity on driving the helical folding behavior of the aryl-triazole foldamer. The temperature-dependent enhanced sampling technique, replica-exchange MD simulations, was employed to understand the folding phenomena. The simulation results show that in a low polarity solvent (dichloromethane), the foldamer prefers to stay in the unfolded state. The unfolded state has four dipolar triazoles (5 D) in their favored all-anti geometries and favoring anti-parallel geometries. However, an increase in solvent polarity using acetonitrile resulted in solvophobic collapse, yielding the helically folded form as the predominant state. The folded helix has an all-syn geometry, with triazoles in parallel arrangements. Intermediate conformations with a mixture of syn and anti arrangements of the triazoles are of lower abundance in both the DCM and MeCN solvents. The chiral handedness of the helix observed experimentally is assigned as left-handed by correlation with computed electronic circular dichroism spectra using time-dependent density functional theory.