The fully‐extended conformation in peptides and proteins

Abstract

The intramolecularly H‐bonded, fully‐extended conformation (C5) of an α‐amino acid residue (and the resulting 2.05‐helix obtained via its propagation) is one of the least extensively investigated types of peptide and protein backbone secondary structure. This situation does still currently occur despite its unique ability to enjoy by far the largest separation per residue among peptide conformations. In this article, we offer a detailed update of our present knowledge on this intriguing 3D‐structure of peptides in the crystal state as obtained from recently published investigations, complemented by a statistical analysis for its occurrence in the crystal structures of α‐amino acid derivatives and peptides available in the Cambridge Structural Database. We have expanded this useful information to the results of a bioinformatics analysis performed on this (so far largely unappreciated) conformation authenticated in all proteins solved by X‐ray diffraction to a resolution of ≤ 1.5 Å. In the last section, we describe the results of our DFT calculations on the conformational preferences of a set of homopeptides (from monomer to octamer) based on as many as six proteins and two noncoded, carefully selected, α‐amino acids. From this literature survey integrated by new energy calculations, we have definitely provided strong support to the thesis that this polypeptide 3D‐structure does indeed exist, it should be not neglected in future studies by structural biochemists, and it represents a very attractive, novel backbone for applications for organic, medicinal, and biomaterials chemists.

Flat, Cα,β‐Didehydroalanine Foldamers with Ferrocene Pendants: Assessing the Role of α‐Peptide Dipolar Moments

“…Both structures are characterized by a fully‐extended conformation of the peptide backbone [8] . All of the φ, ψ, and ω torsion angles, including the ω 0 and ω T torsion angles at the level of the N‐terminal and C‐terminal amide bonds, respectively, show values close to 180° (Supporting Information, Tables S1 and S3).…”

“…[19] Bond distances and bond angles of the ΔAla residues are in general agreement with previously reported values for this C α ,C β unsaturated residue. [7,8] In particular: (i) The average NÀ C α bond distance, 1.399 Å, is significantly shorter than that typical for peptides based on coded amino acids (1.46 Å), [20] whereas the effects of the sp 2 hybridization of the C α atom and the possible π-electron delocalization seem to be less pronounced on the average length of the ΔAla C α À C bond, 1.511 Å, with respect to the corresponding bond in regular peptides (1.53 Å). [20] (ii) The values of the NÀ C α À C bond angle of ΔAla residues, ranging from 107.5°to 109.3°, are significantly compressed with respect to the typical bond angles for an sp 2 hybridized, trisubstituted carbon atom (120°).…”

“…Although, in general, NÀ H•••O=C interactions featuring NÀ H•••O angles less than 120°are not usually considered to be H-bonds, there is spectroscopic and computational evidence for the true H-bond nature of the C 5 structure. [8,21] In addition to the intra-residue NÀ H•••O=C H-bonds, intramolecular CÀ H•••O=C Hbonds are also observed (Figures 6 and 7 and Supporting Information, Tables S2 and S4), each of them involving a hydrogen atom of the ΔAla β-CH 2 group as the donor and the preceding carbonyl oxygen atom as the acceptor. Such a fully extended conformation and the related intramolecular Hbonding network is typical for ΔAla homo-peptides.…”

“…ΔAla is known to preferentially adopt the fully-extended conformation. This 3D-structure, not common in proteins, [8] is also known as 2.0 5 -helix because it is characterized by 2 residues per turn and stabilized by H-bonds encompassing 5-membered pseudo-cycles (Figure 1). [7][8][9] In this peculiar type of helix the rotation per residue along the helix axis is exactly 180°.…”

Conformation control through concurrent N–H⋯S and N–H⋯OC hydrogen bonding and hyperconjugation effects

“…[10][11][12] Recently, there has been an increased awareness of the importance of contributions to secondary structure stabilization from other types of non-covalent interactions, including less conventional H-bonds such as intra-residue C5 H-bonds ( Fig. 1), [13][14][15] or C-H/O interactions, 16,17 as well as phenomena such as n / p* hyperconjugative interactions, 18 Cbonds, 19 cation-p interactions, 20,21 and others. 22 Reports of non-covalent interactions in proteins which specically implicate the side-chain heteroatom of sulfurcontaining residues are rare and do not involve H-bonds; rather, they take the form of sulfur-aromatic interactions 23,24 or chalcogen bonds.…”