The term “peptoids” was introduced decades ago to describe peptide analogues that exhibit better physicochemical and pharmacokinetic properties than peptides. Oligo­(N-substituted glycine) (oligo-NSG) was previously proposed as a peptoid due to its high proteolytic resistance and membrane permeability. However, oligo-NSG is conformationally flexible, and ensuring a defined shape in water is difficult. This conformational flexibility severely limits the biological application of oligo-NSG. Here, we propose oligo­(N-substituted alanine) (oligo-NSA) as a peptoid that forms a defined shape in water. The synthetic method established in this study enabled the first isolation and conformational study of optically pure oligo-NSA. Computational simulations, crystallographic studies, and spectroscopic analysis demonstrated the well-defined extended shape of oligo-NSA realized by backbone steric effects. This new class of peptoid achieves the constrained conformation without any assistance of N-substituents and serves as a scaffold for displaying functional groups in well-defined three-dimensional space in water, which leads to effective biomolecular recognition.

No abstract

De novo design of peptide nanoshapes is of great interest in biomolecular science since the local peptide nanoshapes formed by a short peptide chain in the proteins are often key to the biological activities. Here, we show that the de novo design of peptide nanoshapes with sub-nanometer conformational control can be realized using peptides consisting of N-methyl-L-alanine and N-methyl-D-alanine residues as studied by NMR, X-ray and XFEL crystallographic and computational analyses as well as by direct imaging of the dynamics of the peptide’s nanoshape using cinematographic electron microscopic technique. The conformation of N-methyl-L/D-alanine residue is largely fixed because of the restricted bond rotation, and hence can serve as a scaffold on which we can build a peptide into a designed nanoshape. The local shape control by per-residue conformational restriction by torsional strains starkly contrasts with the global shape stabilization of proteins based on many remote interactions. The oligomers allow the bottom-up design of diverse peptide nanoshapes with a small number of amino acid residues and would offer unique opportunities to realize the de novo design of biofunctional molecules, such as catalysts and drugs.

<div> <div> <div> <p>“Peptoids” was proposed, over decades ago, as a term describing analogs of peptides that exhibit better physicochemical and pharmacokinetic properties than peptides. Oligo-(N-substituted glycines) (oligo-NSG) was previously proposed as a peptoid due to its high proteolytic resistance and membrane permeability. However, oligo-NSG is conformationally flexible and is difficult to achieve a defined shape in water. This conformational flexibility is severely limiting biological application of oligo-NSG. Here, we propose oligo-(N-substituted alanines) (oligo-NSA) as a new peptoid that forms a defined shape in water. A synthetic method established in this study enabled the first isolation and conformational study of optically pure oligo-NSA. Computational simulations, crystallographic studies and spectroscopic analysis demonstrated the well-defined extended shape of oligo-NSA realized by backbone steric effects. The new class of peptoid achieves the constrained conformation without any assistance of N-substituents and serves as an ideal scaffold for displaying functional groups in well-defined three-dimensional space, which leads to effective biomolecular recognition. </p> </div> </div> </div>

<div> <div> <div> <p>“Peptoids” was proposed, over decades ago, as a term describing analogs of peptides that exhibit better physicochemical and pharmacokinetic properties than peptides. Oligo-(N-substituted glycines) (oligo-NSG) was previously proposed as a peptoid due to its high proteolytic resistance and membrane permeability. However, oligo-NSG is conformationally flexible and is difficult to achieve a defined shape in water. This conformational flexibility is severely limiting biological application of oligo-NSG. Here, we propose oligo-(N-substituted alanines) (oligo-NSA) as a new peptoid that forms a defined shape in water. A synthetic method established in this study enabled the first isolation and conformational study of optically pure oligo-NSA. Computational simulations, crystallographic studies and spectroscopic analysis demonstrated the well-defined extended shape of oligo-NSA realized by backbone steric effects. The new class of peptoid achieves the constrained conformation without any assistance of N-substituents and serves as an ideal scaffold for displaying functional groups in well-defined three-dimensional space, which leads to effective biomolecular recognition. </p> </div> </div> </div>