Unconstrained peptoid tetramer exhibits a predominant conformation in aqueous solution

Area of Science:

• Chemical Biology
• Materials Science
• Organic Chemistry

Background:

• Peptoids (N-substituted glycines) are versatile molecules with applications in drug discovery and nanomaterials.
• Conformational control is key for peptoid function, but the solution behavior of unconstrained peptoids is poorly understood.
• Existing studies often focus on conformationally restricted peptoid sequences.

Purpose of the Study:

• To investigate the folding landscape and conformational heterogeneity of simple, unconstrained peptoid tetramers in aqueous solution.
• To develop and apply novel NMR techniques for backbone assignment in peptoids.
• To identify factors influencing the intrinsic conformational preferences of peptoids.

Main Methods:

• Nuclear Magnetic Resonance (NMR) spectroscopy was used to study peptoid tetramers in solution.
• A novel ¹³C-labeling strategy with bromoacetic acid-2-¹³C enabled sequential backbone assignment using the 1,n-Adequate pulse sequence.
• Molecular dynamics simulations complemented NMR data to analyze preferred conformations.

Main Results:

• Two peptoid tetramers containing the N-(2-aminoethyl)glycine (Nae) residue unexpectedly displayed preferred conformations in solution.
• One tetramer predominantly adopted a trans-cis-trans amide bond configuration (52% population), with over 80% of the ensemble featuring a central cis amide bond.
• Analysis indicated that the Nae monomer stabilizes peptoid structure through side-chain-to-main-chain interactions, aligning with peptoid Ramachandran plot predictions.

Conclusions:

• Unconstrained peptoids, particularly those with the Nae monomer, possess significant intrinsic conformational preferences in aqueous solution.
• The Nae residue is identified as a key structural stabilizer, offering a facile route for controlling peptoid conformation.
• These findings facilitate the predictive design of folded peptoid structures for diverse applications, including medicinal chemistry and nanoscience.