Solvent polarity controls the helical conformation of short peptides rich in Calpha-tetrasubstituted amino acids.

The two peptides, rich in C(alpha)-tetrasubstituted amino acids, Ac-Aib-L-(alphaMe)Val-Aib-L-His-NH(2) (1) and Ac-Aib-L-(alphaMe)Val-Aib-O-tBu (2 a) are prevalently helical. They present the unique property of changing their conformation from the alpha- to the 3(10)-helix as a function of the polarity of the solvent: alpha in more polar solvents, 3(10) in less polar ones. Conclusive 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 3(10)-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 3(10)-helix and the use of the CD technique for its assessment.