Sidechain-Backbone Tetrel Bonding Interactions Provide a General Mechanism for trans-Peptoid Stabilization

Cis-trans isomerization of amide bonds impedes de novo design of folded peptoids (poly-N-substituted glycines) with precise secondary structures and affects peptoid-biomolecule binding affinity. Herein, from X-ray, NMR and DFT studies of azapeptoids, we have discovered a tetrel bonding interaction that stabilizes trans-peptoids. We show that peptoids having α-heteroatoms and N-aryl groups in the sidechain adopt trans-amide geometries due to the presence of a n_X /π_Ar →σ*_Cα-N tetrel bonding interaction between the sidechain α-heteroatom lone pair (n_X ) or π-electrons (π_Ar ) and the σ* orbital of the backbone C_α -N bond. Further, CD spectroscopic studies of oligo-proline host-guest model peptides showed that azapeptoid residues stabilize polyproline II helical conformation. These data indicate that the sidechain-backbone tetrel bonding could be leveraged to design peptoids with precise secondary structures for a wide range of biological and material applications.