Oligo(N‐methylalanine) as a Peptide‐Based Molecular Scaffold with a Minimal Structure and High Density of Functionalizable Sites

Abstract

Functionalizable synthetic molecules with nanometer sizes and defined shapes in water are useful as molecular scaffolds to mimic the functions of biomacromolecules and develop chemical tools for manipulating biomacromolecules. Herein, we propose oligo(N-methylalanine) (oligo-NMA) as a peptide-based molecular scaffold with a minimal structure and a high density of functionalizable sites. Oligo-NMA forms a defined shape in water without hydrogen-bonding networks or ring constraints, which enables the molecule to act as a scaffold with minimal atomic composition. Furthermore, functional groups can be readily introduced on the nitrogens and α-carbons of oligo-NMA. Computational and NMR spectroscopic analysis suggested that the backbone structure of oligo-NMA is not largely affected by functionalization. Moreover, the usefulness of oligo-NMA was demonstrated by the design of protein ligands. The ease of synthesis, minimal structure, and high functionalization flexibility makes oligo-NMA a useful scaffold for chemical and biological applications.

Bottom-up design of peptide nanoshapes in water using oligomers of N-methyl-L/D-alanine

“…The energy of each conformer was calculated at the same level and plotted. The generated Ramachandran-type plot of 1 was shown to have a narrow low-energy region around the lowest energy conformer with (f, y) = (-135°, 75°), which is consistent with the previous report 17 (Figure 2a). To understand the stability of the lowest-energy conformer, the conformations at eight local minima including (f, y) = (-135°, 75°) on the Ramachandran-type plot were further geometry optimized without fixing the f and y values and the energies of the optimized conformations were calculated at the B3LYP/6-311G(d) level of theory.…”

“…We first reproduced the Ramachandran-type plot of acetyl-N-methyl-L-alanine dimethylamide (1), a minimal model of L-NMA oligomers, by DFT calculations with minor modifications on the procedures from the previous report. 17 In these calculations, f and y values of 1, which are the two determinants of the conformation of the molecule, were combinatorically rotated from -180° to 180° by 15° and the 625 conformers were geometry optimized by DFT calculations at the B3LYP/6-31G(d) level of theory with implicit water model. The energy of each conformer was calculated at the same level and plotted.…”

“…The conformation of the NMA residue in its oligomers is rigidified by pseudo-1,3-allylic strain, and the oligomer forms a stable extended shape [16][17][18] . These amino acid residues have hence served as attractive building blocks for the bottom-up design of peptide nanoshapes 19,20 .…”