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


Paoli, B. 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 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.

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
Referees:Caflisch A, Hamm P
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:27 March 2009
Deposited On:14 Jan 2010 10:33
Last Modified:05 Apr 2016 13:42
Number of Pages:99
Related URLs:http://opac.nebis.ch/F/?local_base=NEBIS&con_lng=GER&func=find-b&find_code=SYS&request=005885452
Permanent URL: https://doi.org/10.5167/uzh-26725

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