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.
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>
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