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Title: Analysis and prediction of the protein folding nucleus using computational and experimental techniques
Author: Hurley, M. G.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2007
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Two novel algorithms were developed to align pairs of domains according to the conservation of the patterns of physical contacts each residue forms with one another. DPCONTACTS uses only residue contact information while DPCONSTRUCT incorporates secondary structure contact types and environment-specific gap penalities. These algorithms were tested against established structure alignment algorithms based on alignment quality compared to hand-curated family and superfamily alignments. When compared to more established algorithms, both DPCONTACTS and DPCONSTRUCT performed comparatively well. A multiple structure-based sequence alignment algorithm, called MDPCONS, was developed to align and score equivalent positions based on similarities of residue contact patterns. Hand-curated fibronectin type III (FnIII) and I-set family alignments were annotated with experimentally derived key folding positions. When compared with other multiple structure and sequence based alignment algorithms, MDPCONS aligned the majority of β-strands and key folding positions correctly. MDPCONS also scored most key folding positions, highly. An FnIII domain was biophysically characterised and identified to use a novel folding nucleus. Integration of this domain into an FNIII alignment allowed the identification of key folding positions to be tested by MDPCONS. MDPCONS aligned three of the four key folding positions correctly. However, there is no evidence to suggest that residues aligned due to similar patterns of contacts are more likely to be involved in folding than for stability. Finally, statistical coupling analysis was performed for the FnIII and I-set domains to identify if key folding positions are conserved through evolution. The clusters identified were found to be important for establishing and maintaining the structure of the Ig fold and were not involved in conserving the folding nucleus.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available