Right-Handed Helical Foldamers Consisting of De Novo d‑AApeptides

New types of foldamer
scaffolds are formidably challenging to design
and synthesize, yet highly desirable as structural mimics of peptides/proteins
with a wide repertoire of functions. In particular, the development
of peptidomimetic helical foldamers holds promise for new biomaterials,
catalysts, and drug molecules. Unnatural l-sulfono-γ-AApeptides
were recently developed and shown to have potential applications in
both biomedical and material sciences. However, d-sulfono-γ-AApeptides,
the enantiomers of l-sulfono-γ-AApeptides, have never
been studied due to the lack of high-resolution three-dimensional
structures to guide structure-based design. Herein, we report the
first synthesis and X-ray crystal structures of a series of 2:1 l-amino acid/d-sulfono-γ-AApeptide hybrid foldamers,
and elucidate their folded conformation at the atomic level. Single-crystal
X-ray crystallography indicates that this class of oligomers folds
into well-defined right-handed helices with unique helical parameters.
The helical structures were consistent with data obtained from solution
2D NMR, CD studies, and molecular dynamics simulations. Our findings
are expected to inspire the structure-based design of this type of
unique folding biopolymers for biomaterials and biomedical applications.