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Title: A computational analysis of protein-DNA complex structures
Author: Luscombe, Nicholas Makoto
ISNI:       0000 0001 3614 1604
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2000
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Proteins that bind DNA are fundamental to all areas of genetic activity within the cell. To understand how such proteins function, it is necessary to explore the process of recognition and binding to their target DNA sequences. This work presents a comprehensive study of 129 protein-DNA complex structures from the Brookhaven Protein Data Bank and the interactions that are found between the two molecules on binding. NUCPLOT, a software tool that generates schematic plots of intermolecular hydrogen bonds and van der Waals contacts, is described. The resulting diagram is clear, simple and intuitive; it allows immediate identification of the important interactions in the complex and facilitates the study of these structures. NUCPLOT is a completely automated program that can be used for any protein-DNA complex and will also work for certain protein-RNA structures. Also described is a statistical analysis of protein-DNA interactions at an atomic level. Inspection of hydrogen bonds, water-mediated contacts and van der Waals contacts reveals much interdependence between the amino acid and nucleotide base type. These observations are rationalised by inspecting the stereochemistry of the amino acid side chains and base edges exposed in the DNA structure. An interactive Web-based atlas of protein side chain-base contacts is presented as part of the work. Later, the role of the α-helix in DNA-binding by proteins is surveyed - one of the most prevalent methods of direct sequence recognition in the DNA major groove. Comparison of these α-helices from different structural families reveals that there are common binding-orientations between proteins with similar functional requirements. However, examination of the contacts uncovers a very diverse range of interactions between the α-helix and DNA. Finally, sequence conservation in DNA-binding proteins is studied. Amino acids that interact with DNA are generally more conserved than the rest of the protein surface. However, there are significant mutations at key interacting positions, which are expected to discriminate between different DNA sequences. Proteins with comparable structures but alternative functions are explored to see how they have evolved to recognise distinct target sequences and therefore regulate different cellular pathways.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available