Modeling of tertiary and quaternary protein structures
by homology
Inauguraldissertation
zur
Erlangung der Würde eines Doktors der Philosophie
vorgelegt der
Philosophisch-Naturwissenschaftlichen Fakultät der
Universität Basel
von
Florian Kiefer
aus
Freiburg im Breisgau, Deutschland
Basel, 2012
Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von
Prof. Dr. Torsten Schwede
Prof. Dr. Manuel Peitsch
Basel, den 13.12.2011
Prof. Martin Spiess
Dekan
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List of Publications
1-7
1. Bordoli L, Kiefer F, Schwede T. Assessment of disorder predictions in CASP7. Proteins 2007;69
Suppl 8:129-136.
2. Kopp J, Bordoli L, Battey JN, Kiefer F, Schwede T. Assessment of CASP7 predictions for
template-based modeling targets. Proteins 2007;69 Suppl 8:38-56.
3. Bordoli L, Kiefer F, Arnold K, Benkert P, Battey J, Schwede T. Protein structure homology
modeling using SWISS-MODEL workspace. Nat Protoc 2009;4(1):1-13.
4. Kiefer F, Arnold K, Kunzli M, Bordoli L, Schwede T. The SWISS-MODEL Repository and
associated resources. Nucleic Acids Res 2009;37(Database issue):D387-392.
5. Arnold K, Kiefer F, Kopp J, Battey JN, Podvinec M, Westbrook JD, Berman HM, Bordoli L,
Schwede T. The Protein Model Portal. J Struct Funct Genomics 2009;10(1):1-8.
6. Berman HM, Westbrook JD, Gabanyi MJ, Tao W, Shah R, Kouranov A, Schwede T, Arnold K,
Kiefer F, Bordoli L, Kopp J, Podvinec M, Adams PD, Carter LG, Minor W, Nair R, La Baer J. The
protein structure initiative structural genomics knowledgebase. Nucleic Acids Res
2009;37(Database issue):D365-368.
7. Mariani V, Kiefer F, Schmidt T, Haas J, Schwede T. Assessment of template based protein
structure predictions in CASP9. Proteins: Structure, Function, and Bioinformatics
2011;79(S10):37-58.
Abstract
The structure of a protein is crucial to understand its function. Despite this importance,
experimentally solved structures are only available for a small portion of the currently known protein
sequences. Comparative or homology modeling is currently the most powerful method used in order
to predict the structure from sequence by the use of homologous template structures. Models,
hence, need to be accurate regarding their three-dimensional coordinates and must represent the
biological active state of the target protein in order to be useful for scientists.
Four goals are pursued in this work in this area of research. Firstly, we increase the coverage of
homology modeling by introducing a method which is able to identify and align evolutionary distant
template structures. The resulting template search and selection procedure is hierarchical. Closely
related template structures are identified accurately and efficiently by standard tools.
A computationally more complex method is invoked in order to identify evolutionary more distant
template structures with high precision and accuracy. Integrated into an automated modeling
pipeline, the developed method is competitive compared to other protein structure prediction
methods.
Secondly, the automated modeling pipeline is applied to a large set of protein sequences to increase
the structural coverage of sequence space. The resulting models and associated annotation data are
stored in a relational database and can be accessed online in order to allow scientists to query for
their protein of interest. Efforts are made to update a selected set of sequences regularly by
shortening the update process without losing accuracy. It is found that the structural coverage of
seven proteomes is increased considerably by this large scale modeling approach.
Thirdly, the modeling of quaternary structure is addressed. Significant room for improvement in the
field of quaternary structure prediction is found when assessing the current state-of-the-art methods
in a double blind prediction experiment. Novel similarity measures are therefore developed to
distinguish proteins with different quaternary structure. We further create a template library built of
structures in their previously defined most likely oligomeric state, to extent the concept of homology
modeling towards the prediction of oligomeric protein structures. In order to select template
structures which share the same quaternary structure with the target structure, a variety of
evolutionary and structural features are investigated. It is shown, that using a combination of these
features for the first time predicts the quaternary structure with high accuracy.
Finally, the performances of methods which predict non-folded (intrinsically disordered) protein
segments are assessed. Current issues are addressed in a field of very active research as more and
more proteins are found to be hubs in interaction networks with considerable disordered portions in
their tertiary structure. In general it is found that such methods perform well, even within the limits
of the test set.
Contents
1 Introduction.......................................................................................................................... 1
1.1 The importance of protein structures ................................................................................... 1
1.2 Experimental methods to determine protein structures ...................................................... 2
1.3 Resources for protein structures ........................................................................................... 3
1.4 The sequence – structure gap ............................................................................................... 4
1.5 Modeling of protein structures ............................................................................................. 5
1.6 Assessing the accuracy of protein modeling procedures ...................................................... 7
2 Modeling of tertiary protein structures ................................................................................ 11
2.1 The homology modeling approach ...................................................................................... 11
2.1.1 Template identification and alignment with the target sequence ............................. 11
2.1.2 Model building ............................................................................................................. 12
2.1.3 Structural evaluation and assessment ........................................................................ 13
2.1.4 Automated modeling procedures ............................................................................... 13
2.1.5 The SWISS-MODEL system .......................................................................................... 14
2.2 Definition of the Problem .................................................................................................... 15
2.3 Improvement of the SWISS-MODEL homology modeling pipeline ..................................... 15
2.3.1 Template selection procedure .................................................................................... 19
2.3.2 Accuracy of the SWISS-MODEL Pipeline ...................................................................... 20
2.3.3 Discussion .........................................................
