N,N'-Linked Oligoureas as Foldamers: Chain Length Requirements for Helix Formation in Protic Solvent Investigated by Circular Dichroism, NMR Spectroscopy, and Molecular Dynamics
详细信息 查看全文
- 作者：Aude Violette ; Marie Christine Averlant-Petit ; Vincent Semetey ; Christine Hemmerlin ; Richard Casimir ; Roland Graff ; Michel Marraud ; Jean-Paul Briand ; Didier Rognan ; and Gilles Guichard
- 刊名：Journal of the American Chemical Society
- 出版年：2005
- 出版时间：February 23, 2005
- 年：2005
- 卷：127
- 期：7
- 页码：2156 - 2164
- 全文大小：487K
- 年卷期：v.127,no.7(February 23, 2005)
- ISSN：1520-5126
文摘
N,N'-Linked oligoureas with proteinogenic side chains are peptide backbone mimetics belongingto the 
-peptide lineage. In pyridine, heptamer 4 adopts a stable helical fold reminiscent of the 2.614 helicalstructure proposed for -peptide foldamers. In the present study, we have used a combination of CD andNMR spectroscopies to correlate far-UV chiroptical properties and conformational preferences of oligoureasas a function of chain length from tetramer to nonamer. Both the intensity of the CD spectra and NMRchemical shift differences between 
CH2 diastereotopic protons experienced a marked increase for oligomersbetween four and seven residues. No major change in CD spectra occurred between seven and nineresidues, thus suggesting that seven residues could be the minimum length required for stabilizing adominant 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 ureaisomerization occurs, to some degree, along the backbone. Removing unfavorable electrostatic interactionsat 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 furtherdiscussed in light of unrestrained molecular dynamics (MD) simulation. Taken together, these new dataprovide additional insight into the folding propensity of oligoureas in protic solvent and should be of practicalvalue for the design of helical bioactive oligoureas.
-peptide lineage. In pyridine, heptamer 4 adopts a stable helical fold reminiscent of the 2.614 helicalstructure proposed for -peptide foldamers. In the present study, we have used a combination of CD andNMR spectroscopies to correlate far-UV chiroptical properties and conformational preferences of oligoureasas a function of chain length from tetramer to nonamer. Both the intensity of the CD spectra and NMRchemical shift differences between CH2 diastereotopic protons experienced a marked increase for oligomersbetween four and seven residues. No major change in CD spectra occurred between seven and nineresidues, thus suggesting that seven residues could be the minimum length required for stabilizing adominant 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 ureaisomerization occurs, to some degree, along the backbone. Removing unfavorable electrostatic interactionsat 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 furtherdiscussed in light of unrestrained molecular dynamics (MD) simulation. Taken together, these new dataprovide additional insight into the folding propensity of oligoureas in protic solvent and should be of practicalvalue for the design of helical bioactive oligoureas.