NMR-solution structures in methanol of an alpha-heptapeptide, of a beta(3)/beta(2)-nonapeptide, and of an all-beta(3)-icosapeptide carrying the 20 proteinogenic side chains

The NMR-solution structure of an alpha-heptapeptide with a central Aib residue was investigated in order to verify that, in contrast to beta-peptides, short alpha-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 alpha-peptides or proteins was found. A beta(2)/beta(3)-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 beta(2)/beta(3)-nonapeptide with only aliphatic side chains, no dominant conformation could be determined in H2O. Finally, the NMR analysis of a beta(3)-icosapeptide containing the side chains of all 20 proteinogenic amino acids in MeOH is described. It revealed that this 20mer folds into a 3(14)-helix over its whole length forming six full turns, the longest 3(14)-helix found so far. Together, our findings confirm that, in contrast to alpha-peptides, beta-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 beta-peptides is attributed to the conformation-stabilizing effect of the staggered ethane sections in beta-peptides which outweighs the detrimental effect of the increasing macrodipole.