title: Helix-forming propensity of aliphatic urea oligomers incorporating noncanonical residue substitution patterns.
abstract: Aliphatic N,N'-linked oligoureas are peptidomimetic foldamers that adopt a well-defined helical secondary structure stabilized by a collection of remote three-center H-bonds closing 12- and 14-membered pseudorings. Delineating the rules that govern helix formation depending on the nature of constituent units is of practical utility if one aims to utilize this helical fold to place side chains in a given arrangement and elaborate functional helices. In this work, we tested whether the helix geometry is compatible with alternative substitution patterns. The central -NH-CH(R)-CH2-NH-CO- residue in a model oligourea pentamer sequence was replaced by guest units bearing various substitution patterns [e.g., -NH-CH2-CH2-NH-CO-, -NH-CH2-CH(R)-NH-CO-, and -NH-CH(R(1))-CH(R(2))-NH-CO-], levels of preorganization (cyclic vs acyclic residues), and stereochemistries, and the helix formation was systematically assessed. The extent of helix perturbation or stabilization was primarily monitored in solution by Fourier transform IR, NMR, and electronic circular dichroism spectroscopies. Our results indicate that although three new substitution patterns were accommodated in the 2.5-helix, the helical urea backbone in short oligomers is particularly sensitive to variations in the residue substitution pattern (position and stereochemistry). For example, the trans-1,2-diaminocyclohexane unit was experimentally found to break the helix nucleation, but the corresponding cis unit did not. Theoretical calculations helped to rationalize these results. The conformational preferences in this series of oligoureas were also studied at high resolution by X-ray structure analyses of a representative set of modified oligomers.
authors: Université de Bordeaux -CNRS UMR 5248, CBMN, Institut Européen de Chimie et Biologie, 2 rue Robert Escarpit, 33607 Pessac, France.
authors: Nagendar
authors: N
authors: Pendem
authors: Céline
authors: C
authors: Douat
authors: Paul
authors: P
authors: Claudon
authors: Michel
authors: M
authors: Laguerre
authors: Sabine
authors: S
authors: Castano
authors: Bernard
authors: B
authors: Desbat
authors: Dominique
authors: D
authors: Cavagnat
authors: Eric
authors: E
authors: Ennifar
authors: Brice
authors: B
authors: Kauffmann
authors: Gilles
authors: G
authors: Guichard
mesh_terms: D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D003514:Cyclohexylamines / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular; D057786:Peptidomimetics / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017550:Spectroscopy, Fourier Transform Infrared; D014508:Urea / Q000031:analogs & derivatives*
chemical_list: D003514:Cyclohexylamines; D057786:Peptidomimetics; D014508:Urea; C030435:1,2-cyclohexanediamine