The helix-destabilizing propensity scale of D-amino acids: the influence of side chain steric effects

E. Krause, M. Bienert, P. Schmieder, H. Wenschuh

J. Am. Chem. Soc. (2000) 122, 4865-4870

Although D-amino acids are found in various naturally occurring peptides and are frequently used for structure-activity studies, not much is known about their impact on the helical secondary structures formed by L-amino acids. For the first time, this work addresses the effect of the D-enantiomers of the proteinogenic amino acids on the a-helical propensity of peptides containing them. The helix-destabilizing abilities of two adjacent D-amino acids in the peptide sequence H3CCO-KLALKLALXXLKLALKLA-NH2 (X9,10-KLA; X = D-amino acid) were evaluated by means of CD, NMR and reversed-phase HPLC. CD and HPLC data enabled calculation of differences in the free energy of helix formation for D-amino acid (X) relative to glycine (DDGt) or to the corresponding L-amino acid (DDGD-L). The data show that the helix-destabilizing propensity is highly dependent on the amino acid side chain and not related to the structure propensity of the corresponding L-amino acid. In consequence, the D-amino acids can be grouped into (i) weak helix destabilizers (D-His, D-Asp, D-Glu, D-Cys, D-Gln, D-Asn, D-Ser), (ii) medium helix destabilizers (D-Leu, D-Arg, D-Met, D-Lys, D-Trp, D-Ala), and (iii) strong helix destabilizers (D-Thr, D-Phe, D-Val, D-Ile, D-Tyr, D-Pro). Accordingly, the D-isomers of bulky and b-branched amino acids are the most effective in destabilizing the amphipathic KLA-helix by induction of turn-like structures. Such D-isomers disrupt the secondary structure in a manner similar to that of L-proline.