NMR-solution structures in methanol of an α-heptapeptide, of a β³/β²-nonapeptide, and of an all-β³-icosapeptide carrying the 20 proteinogenic side chains

The NMR-solution structure of an α-heptapeptide with a central Aib residue was investigated in order to verify that, in contrast to β-peptides, short α-peptides do not form a helical structures in MeOH. Although the central Aib residue was found to induce a bend in the experimentally determined structure, no secondary structure typical for longer α-peptides or proteins was found. A β²/β³- nonapeptide with polar, positively charged side chains was subjected to NMR analysis in MeOH and H₂O. Whereas, in MeOH, it folds into a 10/12-helix very similar to the structure determined for a corresponding β²/β³-nonapeptide with only aliphatic side chains, no dominant conformation could be determined in H₂O. Finally, the NMR analysis of a β³-icosapeptide containing the side chains of all 20 proteinogenic amino acids in MeOH is described. It revealed that this 20mer folds into a 3₁₄-helix over its whole length forming six full turns, the longest 3₁₄-helix found so far. Together, our findings confirm that, in contrast to α-peptides, β-peptides not only form helices with just six residues, but also form helices that are longer than helical sections usually observed in proteins or natural peptides. The higher helix-forming propensity of long β-peptides is attributed to the conformation-stabilizing effect of the staggered ethane sections in β-peptides which outweighs the detrimental effect of the increasing macrodipole.