Solvent Polarity Controls the Helical Conformation of Short Peptides Rich in C α ‐Tetrasubstituted Amino Acids

The two peptides, rich in C α ‐tetrasubstituted amino acids, Ac‐[Aib‐ L ‐(αMe)Val‐Aib] 2 ‐ L ‐His‐NH 2 ( 1 ) and Ac‐[Aib‐ L ‐(αMe)Val‐Aib] 2 ‐O‐ t Bu ( 2 a ) are prevalently helical. They present the unique property of changing their conformation from the α‐ to the 3 10 ‐helix as a function of the polarity of the solvent: α 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.