Harrison, Paul Martin; (1996) Analysis and prediction of protein structure: Disulphide bridges. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

An analysis of disulphide bridges in protein structure and its application to the prediction of structural features are presented in this thesis. In Chapter 1, amongst other aspects of protein structure and folding, the use of disulphide bridges in the investigation of protein folding and in experimental work that aims to increase the stability of a protein is reviewed. In Chapter 2, the theory of cross-linkage of proteins by disulphides is presented in detail. Chapter 3 describes a procedure to make non-redundant data sets of protein chains that is designed to give as large a data set as possible. Disulphide-bridge connectivity patterns have been analysed and classified (Chapter 4). A classification that takes account of loop lengths, based on the theory of cross-linkage, has been derived. This suggests that the hypothesis that the non-local entropic effect of disulphides is important for small, disulphide-rich proteins cannot be rejected. In Chapter 5, structural principles for disulphide-bridged ß-sheet and for clustered disulphides are described. A motif, comprising two clustered disulphides packed against a ß-hairpin, is characterised and is termed the disulphide cross. It is abundant in small, disulphide-rich proteins and subsumes an array of partial similarities between such protein folds previously identified by several other workers. Aspects of the analysis in Chapter 5 have been applied to the comparative modelling of a growth factor sequentially similar to the epidermal growth factor (EGF), which is a small disulphide-rich protein (Chapter 6). The implications of the modelled structure are discussed in relation to the structures of other EGF-like growth factors and mutagenesis data thereon. Chapter 7 provides general conclusions on the work and suggestions for further developments.

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