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Molecular dynamics studies of the folding of α-helical cross-linked peptides


Paoli, Beatrice. Molecular dynamics studies of the folding of α-helical cross-linked peptides. 2009, University of Zurich, Faculty of Science.

Abstract

Summary The helix-coil transition is the simplest scenario in protein folding. In the last years, the employment of peptides with an attached photoswitchable cross-linker, has been established as an efficient experimental tool to control the helix stability. The observation of a non-exponential kinetics of folding suggested that the system cannot be described simply by a two-state model. In this thesis, molecular dynamics simulations studies at atomic resolution level showed that folding kinetics differ from site to site suggesting a nonco- operative mechanism. Moreover, the free energy profile revealed the presence of multiple folding channels along parallel folding routes that made the over- all kinetics nonexponential. At the end, it was investigated the entanglement effect between bulky side chains and the cross-linker by either replacing the cross-linker with a distance constraint or removing it. In both cases the fold- ing kinetics becomes faster and simpler compared to the cross-linked case. This indicates that the main effect of the cross-linker on the overall kinetics is due to its entanglement with the side chains rather than its effect as a distance constraint.
Zusammenfassung Das einfachste Szenario in der Proteinfaltung ist der Heilx-Coil bergang. Die Faltungskinetik eines Modellpeptids mit einem photoschaltbaren Linker folgt laut zeitaufgelsten Infrarotspektroskopiexperimenten einer gestreckt expo- nentiellen Funktion. In dieser Doktorarbeit wurde durch Molekldynamiksim- ulationen gezeigt, dass der Faltungsprozess nicht kooperativ ist, weil das Pro- fil der freien Energie ungefaltete Minima entlang des Faltungsweges aufweist. Dies ergibt, dass die Faltungsraten ortabhngig sind. Zudem wurde gezeigt, dass die nicht-exponentielle Kinetik eher an der Verschrnkung des Linkers mit den Seitenketten des Peptids als an dessen Effekt als Abstandsbedin- gung liegt.

Abstract

Summary The helix-coil transition is the simplest scenario in protein folding. In the last years, the employment of peptides with an attached photoswitchable cross-linker, has been established as an efficient experimental tool to control the helix stability. The observation of a non-exponential kinetics of folding suggested that the system cannot be described simply by a two-state model. In this thesis, molecular dynamics simulations studies at atomic resolution level showed that folding kinetics differ from site to site suggesting a nonco- operative mechanism. Moreover, the free energy profile revealed the presence of multiple folding channels along parallel folding routes that made the over- all kinetics nonexponential. At the end, it was investigated the entanglement effect between bulky side chains and the cross-linker by either replacing the cross-linker with a distance constraint or removing it. In both cases the fold- ing kinetics becomes faster and simpler compared to the cross-linked case. This indicates that the main effect of the cross-linker on the overall kinetics is due to its entanglement with the side chains rather than its effect as a distance constraint.
Zusammenfassung Das einfachste Szenario in der Proteinfaltung ist der Heilx-Coil bergang. Die Faltungskinetik eines Modellpeptids mit einem photoschaltbaren Linker folgt laut zeitaufgelsten Infrarotspektroskopiexperimenten einer gestreckt expo- nentiellen Funktion. In dieser Doktorarbeit wurde durch Molekldynamiksim- ulationen gezeigt, dass der Faltungsprozess nicht kooperativ ist, weil das Pro- fil der freien Energie ungefaltete Minima entlang des Faltungsweges aufweist. Dies ergibt, dass die Faltungsraten ortabhngig sind. Zudem wurde gezeigt, dass die nicht-exponentielle Kinetik eher an der Verschrnkung des Linkers mit den Seitenketten des Peptids als an dessen Effekt als Abstandsbedin- gung liegt.

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Additional indexing

Item Type:Dissertation (monographical)
Referees:Caflisch Amedeo, Hamm Peter
Communities & Collections:UZH Dissertations
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Place of Publication:Zürich
Date:2009
Deposited On:14 Jan 2010 10:33
Last Modified:24 Sep 2019 16:30
Number of Pages:99
OA Status:Green
Related URLs:https://www.recherche-portal.ch/primo-explore/fulldisplay?docid=ebi01_prod005885452&context=L&vid=ZAD&search_scope=default_scope&tab=default_tab&lang=de_DE (Library Catalogue)

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