Investigation of Framework-forming Aggregation of Peptide Helices on Membrane Surfaces

by Nils Hesselbarth
Doctoral thesis
Date of Examination:2024-11-07
Date of issue:2025-02-14
Advisor:Prof. Dr. Andreas Janshoff
Referee:Prof. Dr. Andreas Janshoff
Referee:Prof. Dr. Konrad Koszinowski
Referee:Prof. Dr. Manuel Alcarazo
Referee:Prof. Dr. Johannes C. L. Walker
Referee:Dr. Holm Frauendorf
Referee:Prof. Dr. Kai Tittmann
Persistent Address: http://dx.doi.org/10.53846/goediss-11093

 

 

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Abstract

English

This study presents the development and investigation of peptide-based systems designed to induce controlled aggregation on membrane surfaces, potentially facilitating cell signaling by promoting lipid raft formation. The peptides were engineered to undergo aggregation upon external stimulation, concentrating cholesterol in specific membrane regions and thus providing a novel strategy for modulating cellular behavior through biomolecular interactions. Key to this work was the rational design and synthesis of peptides with stable α-helical structures, using the AEEEKRK motif to ensure membrane interaction and functional stability. The peptides were synthesized via automated solid-phase peptide synthesis (SPPS), incorporating functional modifications such as fluorophores for tracking and aggregation sites for controlled clustering. Two distinct aggregation mechanisms were explored: metal-ion coordination and disulfide bridge formation. Metal-ion coordination enabled reversible clustering through bipyridine-metal interactions, whereas disulfide bridge formation provided stable, covalent aggregation upon UV exposure. Both systems demonstrated effective membrane anchoring and aggregation, verified through spectroscopic and imaging techniques. While metal-ion coordination offered reversible control, it posed toxicity challenges in biological applications. In contrast, disulfide bridge formation provided robust aggregation but lacked reversibility. This research advances the field of membrane biophysics and cellular signaling, offering potential applications in targeted therapeutic strategies. Future work will focus on optimizing these systems for biological environments, particularly integrating cholesterol for enhanced lipid raft modulation.
Keywords: Peptides; Membrane; SPPS; Aggregation; Alpha-Helix; RIfS; FRAP
 
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