NMR-Structural Investigations of a β3-Dodecapeptide with Proteinogenic Side Chains in Methanol and in Aqueous Solutions

The structural properties of an all-β3-dodecapeptide with the sequence H-β-HLys(Nε-CO(CH2)3-SAcm)-β-HPhe-β-HTyr-β-HLeu-β-HLys-β-HSer-β-HLys-β-HPhe-β-HSer-β-HVal-β-HLys-β-HAla-OH (1) have been studied by two-dimensional homonuclear 1H-NMR and by CD spectroscopy. In MeOH solution, high-resolution NMR spectroscopy showed that the β-dodecapeptide forms an (M)-314-helix, and the CD spectrum corresponds to the pattern expected for an (M)-314-helical secondary structure. In aqueous solution, however, the peptide adopts a predominantly extended conformation without regular secondary-structure elements, which is in agreement with the absence of the characteristic trough near 215 nm in the CD spectrum. The NMR and CD measurements with solutions of 1 in MeOH containing 3M urea further indicated that the peptide retains the regular secondary structural elements under these conditions, whereas, after addition of 40% (v/v) H2O to the MeOH solution, the large 1H-chemical-shift dispersion indicative of a defined spatial peptide fold was lost. The β3-dodecapeptide is – so far – the longest β-peptide shown to adopt a regular (M)-314-helix conformation in an organic solvent. The observation that the structure of this long β3-peptide is not maintained in aqueous solution indicates that the (M)-314-fold is primarily stabilized by short-range interactions.