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

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• 作者：Tim K眉kensh枚ner ; Urs B. Hagemann ; Daniel Wohlwend ; Christina R盲uber ; Tobias Baumann ; Sandro Keller ; Oliver Einsle ; Kristian M. M眉ller ; Katja M. Arndt
• 刊名：Biomacromolecules
• 出版年：2014
• 出版时间：September 8, 2014
• 年：2014
• 卷：15
• 期：9
• 页码：3296-3305
• 全文大小：638K
• ISSN：1526-4602

文摘

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.