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Title: Computational modelling of multidomain proteins with covarying residue pairs
Author: Tetchner, S. J.
ISNI:       0000 0004 8504 0799
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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The vast majority of known protein sequences have no solved three-dimensional structure at all, and the remaining ones usually have not been completely characterised, due to the limitations of experimental structural biology techniques. Structural genomics projects have helped increase the coverage of the protein structure universe, but most available structures still consist of either individual domains or sets of relatively small ones. This has prompted the development of computational methods for protein structure prediction, as well as for multidomain architecture modelling. One appealing idea to achieve this goal consists of detecting residue-residue contacts from multiple sequence alignments, under the assumption that they covary in order to maintain the local microenvironment and the overall stability of protein structures. After early limited success, this type of analysis has lately witnessed substantial progress, thanks to theoretical advances in disentangling genuine from spurious instances of correlation. Unsurprisingly, structural bioinformatics has promptly and successfully applied these improved tools to model globular and transmembrane proteins, along with guiding the assembly of protein complexes. However, the efficacy of these methods in the context of multidomain protein modelling has not yet been investigated. In this thesis state-of-the-art methods for predicting contacts from sequence data have been evaluated and used to build models of two-domain protein structures. Firstly, the ability of alternative methods to identify interdomain contacts was examined in a reference set of experimentally solved structures. Secondly, predicted contacts were employed to score docking models and select near-native solutions accordingly. Finally, predicted contacts were used to guide the assembly of individual domains in a multidomain modelling protocol.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available