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

Area of Science:

• Supramolecular Chemistry
• Organic Chemistry
• Biomaterials Science

Background:

• Cis-trans isomerization of amide bonds in peptoids (poly-N-substituted glycines) hinders the design of specific secondary structures and influences binding affinities with biomolecules.
• Controlling peptoid conformation is crucial for developing novel peptidomimetics and functional materials.

Purpose of the Study:

• To investigate the structural basis for the stabilization of trans-peptoid conformations.
• To identify novel non-covalent interactions that can direct peptoid secondary structures.
• To explore the potential of these interactions for designing functional peptoid-based molecules.

Main Methods:

• X-ray crystallography, Nuclear Magnetic Resonance (NMR) spectroscopy, and Density Functional Theory (DFT) calculations were employed to study azapeptoid structures.
• Circular Dichroism (CD) spectroscopy was used to analyze the conformational effects of azapeptoid residues in oligo-proline peptides.

Main Results:

• A novel tetrel bonding interaction (n_X /π_Ar →σ*_Cα-N) was identified, stabilizing trans-amide geometries in peptoids with α-heteroatoms and N-aryl sidechains.
• This interaction involves the lone pair of the sidechain α-heteroatom or π-electrons from the N-aryl group and the σ* orbital of the backbone C_α -N bond.
• Azapeptoid residues were shown to stabilize the polyproline II helical conformation in model peptides.

Conclusions:

• Sidechain-backbone tetrel bonding is a key interaction for stabilizing trans-peptoid conformations.
• This discovery provides a new strategy for designing peptoids with predictable secondary structures.
• The findings have significant implications for the development of peptoids in diverse biological and material science applications.