Solvent polarity controls the helical conformation of short peptides rich in C-a-tetrasubstituted amino acids

The two peptides, rich in Ca-tetrasubstituted amino acids, Ac-[Aib-L-(aMe)Val-Aib]2-L-His-NH2 (1) and Ac-[Aib-L-(aMe)Val-Aib]2-O-tBu (2a) are prevalently helical. They present the unique property of changing their conformation from the alpha- to the 310- helix as a function of the polarity of the solvent: alpha in more polar solvents, 310 in less polar ones. Concl usive evidence of this reversible change of conformation is reported on the basis of the circular dichroism (CD) spectra and a detailed two-dimensional NMR analysis in two solvents (trifluoroethanol and methanol) refined with molecular dynamics calculations. The X-ray diffractometric analysis of the crystals of both peptides reveals that they assume a prevalent 310-helix conformation in the solid state. This conformation is practically superimposable on that obtained from the NMR analysis of 1 in methanol. The NMR results further validate the reported CD signature of the 310-helix and the use of the CD technique for its assessment.