The Helix-Destabilizing Propensity Scale of d-Amino Acids:  The Influence of Side Chain Steric Effects

• Published in: Journal of the American Chemical Society 2000-05, Vol.122 (20), p.4865-4870
• Main Authors: Krause, Eberhard, Bienert, Michael, Schmieder, Peter, Wenschuh, Holger
• Format: Article
• Language: English
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja9940524

Although d-amino acids are found in various naturally occurring peptides and frequently used for structure−activity studies, not much is known about their impact on the helical secondary structures formed by l-amino acids. Although several previous accounts reported on the α-helical propensity of l-amino acids, the present contribution addresses this subject for the first time for the corresponding d-enantiomers of all of the proteinogenic amino acids. Thus, the helix-destabilizing abilities of the 19 d-amino acids in the host sequence acetyl-KLALKLALxxLKLALKLA-amide (x9,10-KLA) were evaluated by means of circular dichroism (CD) spectroscopy, nuclear magnetic resonance, 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 (ΔΔG t) or to the corresponding l-amino acid (ΔΔG d-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 β-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.