Expanding the polypeptide backbone: hydrogen-bonded conformations in hybrid polypeptides containing the higher homologues of α-amino acids

Abstract

Half a century has passed since the hydrogen-bonded secondary structures of polypeptides and proteins were first recognized. An extraordinary wealth of conformational information is now available on peptides and proteins, which are formed of a-amino acid residues. More recently, the discovery of well-folded structures in oligopeptides containing b-amino acids has focused a great deal of current interest on the conformational properties of peptides constructed from higher homologues (u) of a-amino acids. This review examines the nature of intramolecularly hydrogen-bonded conformations of hybrid peptides formed by amino acid residues, with a varying number of backbone atoms. The b-turn, a ubiquitous structural feature formed by two residue (aa) segments in proteins and peptides, is stabilized by a 10-atom (C 10 ) intramolecular 4/1 hydrogen bond. Hybrid turns may be classified by comparison with their aa counterparts. The available crystallographic information on hydrogen-bonded hybrid turns is surveyed in this review. Several recent examples demonstrate that individual u-amino acid residues and hybrid dipeptide segments may be incorporated into the regular structures of a-peptides. Examples of both peptide helices and hairpins are presented. The present review explores the relationships between folded conformations in hybrid sequences and their counterparts in all a-residue sequences. The use of stereochemically constrained u-residues promises to expand the range of peptide design strategies to include u-amino acids. This approach is exemplified by well-folded structures like the C 12 (ag) and C 14 (gg) helices formed in short peptides containing multiply substituted g-residues. The achiral g-residue gabapentin is a readily accessible building block in the design of peptides containing g-amino acids. The construction of globular polypeptide structures using diverse hybrid sequences appears to be a realistic possibility.

Interplay among side chain sequence, backbone composition, and residue rigidification in polypeptide folding and assembly

“…Such efforts have included the study of RNA analogues based on pyranose rather than furanose (3), peptides based on ␤-or ␥-amino acids rather than ␣-amino acids (4,5), and systems that diverge more profoundly from biological precedents (6,7). As the folding propensities of new backbone elements have been elucidated, the first steps have been taken to blend natural and unnatural subunits and thereby create folded oligomers with heterogeneous backbones and distinctive behavior (8)(9)(10).…”

Synthesis of Chemically Modified Bioactive Peptides: Recent Advances, Challenges and Developments for Medicinal Chemistry

“…Due to the elongated backbone, b-amino acids offer a large possibility of derivatizations, particularly because they can have more than one side chain [113]. If b-amino acids are involved in turns, these turns are also extended; hence they are called pseudoturns and are given the prefix y. Peptides containing b-homologues of a-amino acids can form pronounced turn structures, especially if the backbone is constrained by the residues [106]. When introduced into a cyclic peptide, b-amino acids are able to strongly induce secondary structure elements.…”

Disfavoring Macrocycle b Fragments by Constraining Torsional Freedom: The “Twisted” Case of QWFGLM b6

“…Due to its secondary amine structure, the proline residue adopts a fixed dihedral angle (~60°) in peptides on its Nterminal side [44]. In addition, proline is an endocyclic fivemembered ring which introduces rigidity because no bond rotation is possible over the C(⟼)-N bond.…”