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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

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 noncooperative mechanism. Moreover, the free energy profile revealed the presence of multiple folding channels along parallel folding routes that made the overall 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 folding 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 exponentiellen Funktion. In dieser Doktorarbeit wurde durch Molekldynamiksimulationen gezeigt, dass der Faltungsprozess nicht kooperativ ist, weil das Profil 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 Abstandsbedingung liegt.

Abstract

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 noncooperative mechanism. Moreover, the free energy profile revealed the presence of multiple folding channels along parallel folding routes that made the overall 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 folding 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 exponentiellen Funktion. In dieser Doktorarbeit wurde durch Molekldynamiksimulationen gezeigt, dass der Faltungsprozess nicht kooperativ ist, weil das Profil 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 Abstandsbedingung liegt.

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Additional indexing

Item Type:Dissertation (monographical)
Referees:Caflisch Amedeo, Hamm Peter
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry

07 Faculty of Science > Department of Chemistry
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:15 Apr 2021 14:03
Number of Pages:99
OA Status:Green
Other Identification Number:urn:nbn:ch:bel-279181

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