N,N'-linked oligoureas as foldamers: chain length requirements for helix formation in protic solvent investigated by circular dichroism, NMR spectroscopy, and molecular dynamics.
N,N'-linked oligoureas with proteinogenic side chains are peptide backbone mimetics belonging to the gamma-peptide lineage. In pyridine, heptamer 4 adopts a stable helical fold reminiscent of the 2.6(14) helical structure proposed for gamma-peptide foldamers. In the present study, we have used a combination of CD and NMR spectroscopies to correlate far-UV chiroptical properties and conformational preferences of oligoureas as a function of chain length from tetramer to nonamer. Both the intensity of the CD spectra and NMR chemical shift differences between alphaCH2 diastereotopic protons experienced a marked increase for oligomers between four and seven residues. No major change in CD spectra occurred between seven and nine residues, thus suggesting that seven residues could be the minimum length required for stabilizing a dominant conformation. Unexpectedly, in-depth NMR conformational investigation of heptamer 4 in CD3OH revealed that the 2.5 helix probably coexists with partially (un)folded conformations and that Z-E urea isomerization occurs, to some degree, along the backbone. Removing unfavorable electrostatic interactions at the amino terminal end of 4 and adding one H-bond acceptor by acylation with alkyl isocyanate (4 --> 7) was found to reinforce the 2.5 helical population. The stability of the 2.5 helical fold in MeOH is further discussed in light of unrestrained molecular dynamics (MD) simulation. Taken together, these new data provide additional insight into the folding propensity of oligoureas in protic solvent and should be of practical value for the design of helical bioactive oligoureas.
Violette
Aude
A
UPR 9021 CNRS-Immunologie et Chimie Thérapeutiques (ICT), Institut de Biologie Moléculaire et Cellulaire, 15 rue René Descartes, F-67084 Strasbourg Cedex, France.
Averlant-Petit
Marie Christine
MC
Semetey
Vincent
V
Hemmerlin
Christine
C
Casimir
Richard
R
Graff
Roland
R
Marraud
Michel
M
Briand
Jean-Paul
JP
Rognan
Didier
D
Guichard
Gilles
G
D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry; D002942:Circular Dichroism; D008958:Models, Molecular; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000737:chemistry*; D012997:Solvents; D013816:Thermodynamics; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry
D010455:Peptides; D012997:Solvents; D014508:Urea