Dokument: Exploring the Free Energy Landscape and Conformational Dynamics of Intrinsically Disordered Proteins and Amyloid Aggregation
| Titel: | Exploring the Free Energy Landscape and Conformational Dynamics of Intrinsically Disordered Proteins and Amyloid Aggregation | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=70517 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20250825-163445-8 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Schäffler, Moritz [Autor] | |||||||
| Dateien: |
| |||||||
| Beitragende: | Prof. Dr. Strodel, Birgit [Gutachter] Prof. Dr. Gohlke, Holger [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 540 Chemie | |||||||
| Beschreibung: | Intrinsically disordered proteins (IDPs) play a pivotal role in amyloid aggregation, a process linked to neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Due to their flexible structures, IDPs can transition from disordered to ordered states upon
interaction with molecular partners, often leading to the formation of amyloid fibrils. This thesis examines the mechanisms of IDP conformation switching and aggregation using molecular dynamics (MD) simulations and free energy surface (FES) analyses to elucidate structural transitions, fibrillization pathways and early aggregation events, i.e. oligomer formation. In this work, three IDPs involved in amyloid formation are studied: the amyloid-β protein (Aβ42 ), a segment of the parathyroid hormone (PTH1−34 ), and the SH3 domain of the bovine phosphatidylinositol-3-kinase (PI3K-SH3). For Aβ42 , we analyze its configurational space in various molecular environments, highlighting its transition from a disordered state to a toxic β-hairpin structure. By employing transition networks and FES calculations, we reveal that Aβ42 as a monomer in solution exhibits a ’structurally inverted folding funnel’, where disordered states dominate. Upon dimerization, the FES resembles that of a folded protein, with a singular folding funnel and a β-hairpin structure at the global minimum. A similar change in the FES is observed if Aβ42 interacts with either a glycoseaminoglycan or lipids, which both promote the formation of intra-peptide β-sheets. For PTH25−37 , we study photoinduced reversible amyloid fibrillization by incorporating a photoswitch, 3-[(4-aminomethyl)phenyl]diazenylbenzoic acid, at various positions in the peptide. Through computational design, synthesis, and experimental validation, we demonstrate how the mutation position impacts fibril formation and develop a comprehensive fibril model for PTH25−37 and one of its mutants. In this study, we demonstrate how light-induced switching between the cis and trans conformations of the photoswitch enables controlled, reversible transitions between an amorphous state (cis) and fibril formation (trans). These structural propensities are further explained through comprehensive MD simulations. Lastly, we investigate pH-dependent amyloid aggregation in the context of the PI3K-SH3 domain. Using extensive MD simulations, we elucidate the structural transition from a folded state at neutral pH to a disordered state at acidic pH, which drives amyloid formation. Our analysis identifies key features of pH-driven unfolding and aggregation, providing a framework for future experimental validation. In summary, this thesis offers insights into IDP behavior during amyloid aggregation, focusing on disorder-to-order transitions and FES changes across different environments. Additionally, we examine the role of pH and photo-controlled aggregation in modulating fibril formation, shedding light on key features driving these processes. | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät | |||||||
| Dokument erstellt am: | 25.08.2025 | |||||||
| Dateien geändert am: | 25.08.2025 | |||||||
| Promotionsantrag am: | 16.09.2021 | |||||||
| Datum der Promotion: | 13.06.2025 |
