Amino acid modifications for conformationally constraining naturally occurring and engineered peptide backbones: Insights from the Protein Data Bank

Abstract

Extensive efforts invested in understanding the rules of protein folding are now being applied, with good effect, in de novo design of proteins/peptides. For proteins containing standard α‐amino acids alone, knowledge derived from experimentally determined three‐dimensional (3D) structures of proteins and biologically active peptides are available from the Protein Data Bank (PDB), and the Cambridge Structural Database (CSD). These help predict and design protein structures, with reasonable confidence. However, our knowledge of 3D structures of biomolecules containing backbone modified amino acids is still evolving. A major challenge in de novo protein/peptide design concerns the engineering of conformationally constrained molecules with specific structural elements and chemical groups appropriately positioned for biological activity. This review explores four classes of amino acid modifications that constrain protein/peptide backbone structure. Systematic analysis of peptidic molecule structures (eg, bioactive peptides, inhibitors, antibiotics, and designed molecules), containing these backbone‐modified amino acids, found in the PDB and CSD are discussed. The review aims to provide structure–function insights that will guide future design of proteins/peptides.

A ribosomally synthesised and post-translationally modified peptide containing a β-enamino acid and a macrocyclic motif

“…It is known that peptides containing dehydroamino acid residues tend to be 2.0 5 -helix, meaning that the helix is 2 residues per turn and stabilised by H-bonds encompassing 5-membered pseudo-cycles between NH and the carbonyl of the same amino acid residue (Supplementary Fig. 54) [33][34][35] . As a result, dehydroamino acid residues stretches are arrange in an extended conformation.…”