%0 Journal
%T The Helix-Destabilizing Propensity Scale of d-Amino Acids:  The Influence of Side Chain Steric Effects
%A Eberhard Krause, Michael Bienert, Peter Schmieder, and Holger Wenschuh
%J Journal of the American Chemical Society
%V 122
%P 4865-4870
%D 2000
%R https://doi.org/10.1021/ja9940524
%X 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 (ΔΔGt) or to the corresponding l-amino acid (ΔΔGd-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.