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Title: Structural modelling of transmembrane domains
Author: Kelm, Sebastian
ISNI:       0000 0004 2722 192X
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2011
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Membrane proteins represent about one third of all known vertebrate proteins and over half of the current drug targets. Knowledge of their three-dimensional (3D) structure is worth millions of pounds to the pharmaceutical industry. Yet experimental structure elucidation of membrane proteins is a slow and expensive process. In the absence of experimental data, computational modelling tools can be used to close the gap between the numbers of known protein sequences and structures. However, currently available structure prediction tools were developed with globular soluble proteins in mind and perform poorly on membrane proteins. This thesis describes the development of a modelling approach able to predict accurately the structure of transmembrane domains of proteins. In this thesis we build a template-based modelling framework especially for membrane proteins, which uses membrane protein-specific information to inform the modelling process.Firstly, we develop a tool to accurately determine a given membrane protein structure's orientation within the membrane. We offer an analysis of the preferred substitution patterns within the membrane, as opposed to non-membrane environments, and how these differences influence the structures observed. This information is then used to build a set of tools that produce better sequence alignments of membrane proteins, compared to previously available methods, as well as more accurate predictions of their 3D structures. Each chapter describes one new piece of software or information and uses the tools and knowledge described in previous chapters to build up to a complete accurate model of a transmembrane domain.
Supervisor: Deane, Charlotte M. ; Shi, Jiye Sponsor: Biotechnology and Biological Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Bioinformatics (biochemistry) ; Bioinformatics (life sciences) ; Membrane proteins ; Crystallography ; Applications and algorithms ; Program development and tools ; Software engineering ; Molecular biophysics (biochemistry) ; membrane proteins ; protein structure ; protein modelling ; three-dimensional structure prediction ; membrane insertion ; environment-specific substitution tables ; loop modelling