| dc.contributor.advisor | Groot, Bert de Prof. Dr. | |
| dc.contributor.author | Peters, Jan Henning | |
| dc.date.accessioned | 2014-03-26T10:41:04Z | |
| dc.date.available | 2014-03-26T10:41:04Z | |
| dc.date.issued | 2014-03-26 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-0022-5E6D-E | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-4429 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/ | |
| dc.subject.ddc | 571.4 | de |
| dc.title | On the Effect of Binding on Ubiquitin Dynamics | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Groot, Bert de Prof. Dr. | |
| dc.date.examination | 2013-04-02 | |
| dc.description.abstracteng | Protein-protein interactions play an important role in all biological processes.
But the principles underlying these interactions are not yet fully
understood. Ubiquitin is a small signalling protein that non-covalently interacts
with and is recognised by a multitude of other proteins. I have
conducted molecular dynamics simulations of ubiquitin in complex with 12
different binding partners and compared ensembles of bound and unbound
ubiquitin to determine the influence of complex formation on the dynamic
properties of this protein. Along the main mode of fluctuation of ubiquitin,
binding in most cases reduces the conformational space available to ubiquitin
to a characteristic subspace of that covered by unbound ubiquitin. This
behaviour can be well explained using the model of conformational selection.
For lower amplitude collective modes, a spectrum of zero to almost
complete coverage of bound by unbound ensembles was observed. The significant
differences between bound and unbound structures are exclusively
situated at the binding interface. Overall, the findings correspond neither
to a complete conformational selection nor induced fit scenario. Instead, I
introduce a model of conformational restriction, extension and shift, which
describes the full range of observed effects. The observation of characteristic
restrictions of the main mode dynamics in complexes, lead me to develop
the hypothesis that ubiquitin binding can be modulated by changing main
mode behaviour, for example by mutation of residues in the hydrophobic
core. Using a screening protocol based on non-equilibrium free energy simulations,
eleven mutations of ubiquitin were identified that shift the equilibrium
population of unbound ubiquitin along the main mode. I calculated
the effect of these mutations on the free energy of binding to different binding
partners that require ubiquitin to be a characteristic state, observing a
significant shift in binding affinity. | de |
| dc.contributor.coReferee | Griesinger, Christian Prof. Dr. | |
| dc.subject.eng | Ubiquitin | de |
| dc.subject.eng | Molecular Dynamics | de |
| dc.subject.eng | Protein-Protein Interaction | de |
| dc.subject.eng | Binding | de |
| dc.subject.eng | Conformational Dynamics | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-0022-5E6D-E-2 | |
| dc.affiliation.institute | Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.identifier.ppn | 781601002 | |