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

The two peptides, rich in C-alpha-tetrasubstituted amino acids, Ac-[Aib-L-(alpha Me)Val-Aib](2)-L-His-NH2 (1) and Ac-[Aib-L-(alpha Me)Val-Aib](2)-O-tBu (2a) 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 con-formation 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 I 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.