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 alpha-heteroatoms and N-aryl groups in the sidechain adopt trans-amide geometries due to the presence of a n(X)/pi(Ar)->sigma*(C alpha-N) tetrel bonding interaction between the sidechain alpha-heteroatom lone pair (n(X)) or pi-electrons (pi(Ar)) and the sigma* orbital of the backbone C-alpha-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.

Automated summary

From X-ray, NMR, and DFT studies of azapeptoids, a tetrel bonding interaction that stabilizes trans-peptoids has been discovered. Peptoids with alpha-heteroatoms and N-aryl groups in the sidechain adopt trans-amide geometries due to the tetrel bonding interaction between the sidechain alpha-heteroatom lone pair or pi-electrons and the sigma* orbital of the backbone C-alpha-N bond. CD spectroscopic studies of oligo-proline host-guest model peptides also showed that azapeptoid residues stabilize polyproline II helical conformation.