Analysis of Selected and Designed Chimeric D- and L-alpha-Helix Assemblies

作者：Kuekenshoener Tim; Hagemann Urs B; Wohlwend Daniel; Raeuber Christina; Baumann Tobias; Keller Sandro; Einsle Oliver; Mueller Kristian M; Arndt Katja M^*

来源：Biomacromolecules, 2014, 15(9): 3296-3305.

DOI：10.1021/bm5006883

D-Peptides have been attributed pharmacological advantages over regular L-peptides, yet design rules are largely unknown. Based on a designed coiled coil-like D/L heterotetramer, named L-Base/D-Acid, we generated a library offering alternative residues for interaction with the D-peptide. Phage display selection yielded one predominant peptide, named HelixA, that differed at 13 positions from the scaffold helix. In addition to the observed D-/L-heterotetramers, ratio-dependent intermediate states were detected by isothermal titration calorimetry. Importantly, the formation of the selected HelixA/D-Acid bundle passes through fewer intermediate states than L-Base/D-Acid. Back mutation of HelixA core residues to L-Base (HelixLL) revealed that the residues at e/g-positions are responsible for the different intermediates. Furthermore, a Val-core variant (PeptideVV) was completely devoid of binding D-Acid, whereas an Ile-core helix (HelixII) interacted with D-Acid in a significantly more specific complex than L-Base.

• 出版日期2014-9