Conformational sampling of bioactive conformers: a low-temperature NMR study of 15N-Leu-enkephalin.
Conformational studies of enkephalins are hampered by their high flexibility which leads to mixtures of quasi-isoenergetic conformers in solution and makes NOEs very difficult to detect in NMR spectra. In order to improve the quality of the NMR data, Leu-enkephalin was synthesized with 15N-labelled uniformly on all amide nitrogens and examined in a viscous solvent medium at low temperature. HMQC NOESY spectra of the labelled Leu-enkephalin in a DMSOd6/H2O) mixture at 275 K do show numerous NOEs, but these are not consistent with a single conformer and are only sufficient to describe the conformational state as a mixture of several conformers. Here a different approach to the structure-activity relationships of enkephalins is presented: it is possible to analyse the NMR data in terms of limiting canonical structures (i.e. beta- and gamma-turns) and finally to select only those consistent with the requirements of delta selective agonists and antagonists. This strategy results in the prediction of a family of conformers that may be useful in the design of new delta selective opioid peptides.
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Istituto Chimica Molecole di Interesse Biologico (associated to the Italian National Institute for the Chemistry of Biological Systems), CNR, Arco Felice, Italy.
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D003080:Cold Temperature; D004743:Enkephalin, Leucine / Q000737:chemistry* / Q000502:physiology; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008958:Models, Molecular; D009587:Nitrogen Isotopes; D011487:Protein Conformation; D012984:Software; D013329:Structure-Activity Relationship; D014102:Torsion Abnormality
D009587:Nitrogen Isotopes; D004743:Enkephalin, Leucine