Protein complexes structure prediction by combination of binary interactions derived by homology [Elektronische Ressource] / presented by Matthieu Pichaud

English
144 Pages
Read an excerpt
Gain access to the library to view online
Learn more

Description

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.................

Subjects

Informations

Published by
Published 01 January 2008
Reads 9
Language English
Document size 14 MB
Report a problem

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 the most from this
time in room V115: “Privet”, “Sacrebleu” or “La Java Bleue”.

I am very grateful to the members of my Thesis Advisory Committee, Prof. Dr. Irmi
Sinning, Dr. Elena Conti and Dr. Carsten Schultz for their invaluable help and care,
not only scientific.

Thanks also to Prof. Dr. Kummer and Dr. Anne-Claude Gavin for making me the
honor of joining my Thesis Defense Committee.

I would like to thank the people who kindly spent a great amount of their time
reading and enriching this essay of their comments, Mirana, Julie, Stu, Erik,
Damien, Victor, Matthew, Chad and Rob. More than connections, I have learned a
lot from their remarks (‘for that’ is now banned from my speech).

Last but not least, I would like to thank my family, my ‘family’ from Heidelberg,
Isabelle and my friends for their warm and kind support. Without them, the task
would have been even harder and these years far less fun.
iv Publications
Publications

Publication 1:
A structural perspective on protein-protein interactions. Russell RB, Alber F, Aloy P,
Davis FP, Korkin D, Pichaud M, Topf M, Sali A. Curr Opin Struct Biol. 2004 Jun;
14(3):313-24. Review.

Publication 2:
Protein complexes: structure prediction challenges for the 21st century. Aloy P,
Pichaud M, Russell RB. Curr Opin Struct Biol. 2005 Feb; 15(1):15-22. Review.
v