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

  • 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.

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Metadaten
Author:Tim Kuekenshoener, Urs B. Hagemann, Daniel Wohlwend, Christina Raeuber, Tobias Baumann, Sandro Keller, Oliver Einsle, Kristian M. Mueller, Katja Maren ArndtORCiDGND
DOI:https://doi.org/10.1021/bm5006883
ISSN:1525-7797 (print)
ISSN:1526-4602 (online)
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=25072521
Parent Title (English):Biomacromolecules : an interdisciplinary journal focused at the interface of polymer science and the biological sciences
Publisher:American Chemical Society
Place of publication:Washington
Document Type:Article
Language:English
Year of first Publication:2014
Year of Completion:2014
Release Date:2017/03/27
Volume:15
Issue:9
Pagenumber:10
First Page:3296
Last Page:3305
Funder:Collaborative Research Centre, in the Emmy-Noether Program of the German Research Foundation (DFG) [(SFB) 850, Ar 373]; European Research Council
Organizational units:Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie
Peer Review:Referiert