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Informations
Publié par | ruprecht-karls-universitat_heidelberg |
Publié le | 01 janvier 2008 |
Nombre de lectures | 9 |
Langue | English |
Poids de l'ouvrage | 14 Mo |
Extrait
Dissertation
Submitted to the
Combined Faculties for the Natural Sciences and for Mathematics of the Ruperto-
Carola University of Heidelberg, Germany
For the degree of
Doctor of Natural Sciences
Protein Complexes Structure Prediction by
Combination of Binary Interactions Derived
by Homology
presented by
Graduate Engineer: Matthieu Pichaud
Dissertation
Submitted to the
Combined Faculties for the Natural Sciences and for Mathematics of the Ruperto-
Carola University of Heidelberg, Germany
For the degree of
Doctor of Natural Sciences
presented by
Graduate Engineer: Matthieu Pichaud
Born in: Nantes, France
Oral examination: ________________
Protein Complexes Structure Prediction by
Combination of Binary Interactions Derived
by Homology
Referees: Dr. Elena Conti
Prof. Dr. Irmgard Sinning
Willst du ins Unendliche schreiten,
Geh nur im Endlichen nach allen seiten.
Johann Wolfgang von Goethe Table of contents
Table of contents
Table of contents.................................................................................................... i
Acknowledgments.................................................................................................iv
Publications ...........................................................................................................v
Zusammenfassung.................................................................................................vi
Abstract................................................................................................................. 1
Introduction .......................................................................................................... 3
1. The protein complex, one level of biological organization .......................... 3
2. Protein structures ........................................................................................ 3
2.1. Tertiary structure .................................................................................. 3
2.2. Quaternary structure............................................................................. 5
3. Determining protein structure...................................................................... 6
3.1. Protein over-expression ........................................................................ 6
3.2. X-ray crystallography............................................................................ 7
3.3. Nuclear Magnetic Resonance (NMR) .................................................... 8
3.4. Electron Microscopy (EM)..................................................................... 9
3.5. Small-angle Scattering (SAS) ................................................................. 9
3.6. Electron tomography........................................................................... 10
3.7. Hybrid approaches............................................................................. 10
4. Towards a structural determination of protein complexes.......................... 11
4.1. Determination of the composition of a protein complex...................... 11
4.2. Prediction of protein structure............................................................. 21
4.3. Detection of domains ......................................................................... 23
4.4. Prediction of the structure of a protein assembly ................................. 25
5. The problem ............................................................................................. 33
Material and Methods ......................................................................................... 34
1. Overview of the method ........................................................................... 34
2. Collecting interaction templates ................................................................ 36
2.1. Comparison of interaction templates using iRMSD.............................. 36
2.2. Inventory and selection of interaction templates ................................. 37
2.3. Database schema ............................................................................... 38
i Table of contents
2.4. Maintenance ...................................................................................... 40
3. Getting annotated structures for each domain ........................................... 41
3.1. From sequence to structural models.................................................... 41
3.2. Assigning domains to a protein........................................................... 42
4. Program.................................................................................................... 43
4.1. The basic search procedure ................................................................ 43
4.2. Making the best use of prior information............................................. 54
4.3. Looking for specific features ............................................................... 55
4.4. Exploring and understanding the predictions....................................... 59
5. Benchmark sets......................................................................................... 61
5.1. Comparison of multi-domain structures .............................................. 62
5.2. Triplets ............................................................................................... 63
5.3. Sets of complexes of known structure that can theoretically be built
from pieces.................................................................................................. 67
6. Potential applications in unsolved complexes ........................................... 67
Results ................................................................................................................ 70
1. Evaluation of the procedure – Benchmark ................................................. 70
1.1. Results from the triplet dataset ............................................................ 70
1.2. Evaluation of known complexes that can presumably be built from
pieces .......................................................................................................... 74
1.3. Multidomain polypeptide chain: Gelatinase A .................................... 78
1.4. Dimerisation: EF-Tu/EF-Ts................................................................... 79
1.5. Creation of interactions not in original structure: CDK6/cyclin
D/INK4 complex.......................................................................................... 81
1.6. Highly symmetrical structures............................................................. 83
2. Applications.............................................................................................. 87
2.1. Estimation of the applicability of the method at different time points... 87
2.2. Predictions ......................................................................................... 88
Discussion ........................................................................................................ 103
1. Summary of the results............................................................................ 103
1.1. Results.............................................................................................. 103
1.2. Application....................................................................................... 104
ii Table of contents
1.3. Comments........................................................................................ 104
2. Comparison with combinatorial docking................................................. 111
3. Other potential uses of protein interactions ............................................. 114
3.1. Prediction of interfaces ..................................................................... 114
3.2. Limiting the number of structural determinations required for
predicting assemblies................................................................................. 114
3.3. Spatial constraints............................................................................. 115
3.4. A glimpse at the stoichiometry of any complex................................. 118
4. Conclusion ............................................................................................. 119
References ........................................................................................................ 120
iii Acknowledgments
Acknowledgments
First of all, I would like to thank Dr. Rob Russell, my supervisor, for introducing me
to the fascinating world of protein structures. His vast knowledge, his enthusiasm
for emerging ideas and his encouragements contributed immensely to the success
of this Ph.D.
Many thanks to all the members of the Russell group for their great support,
interesting discussions, inspiring advices and mainly for making the atmosphere so
nice and stimulating. It is hard for me to know what I will miss