Karmirantzou, Maria; (1999) Computational approaches to protein ligand interactions: Protein haem complexes. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Many different proteins bind and utilise haem to perform important biological functions; the aim of this work was to gain an understanding of some of the underlying molecular recognition processes. We considered how the protein environment determines haem binding, and what are the consequences for ligand conformation. Sets of homologous globins and of non-homologous haem-binding proteins were chosen on the basis of sequence and structural similarity, allowing us to compare ligand conformation and to explore the factors that modulate its structure. Comparison of bound and un-bound haems revealed a conformational disparity between the data-sets, suggesting that protein structural factors provide the dominant effect over the conformational features of the ligand. Even in the homologous globins, the ligand side-chain conformation is variable; greater variability within the non-homologous group reflects different local amino acid sequences of their binding pockets. Moreover, the haem skeleton can be severely distorted, being particularly sensitive to local environment, to attached molecules, and to ligation state. The haem environment was analysed to understand its role in the functional and structural variability of the ligand. Predominance of mainly-alpha structures characterises haemoproteins. While the binding sites are radically different in topology, there are preferred binding modes, with the ligand side-chains engaged in a network of hydrophobic and hydrogen bonding interactions. The stacking of aromatic side-chains on the haem skeleton also appears to be essential in the formation of protein-ligand complexes. Analysis of the haem interface revealed that specific residues prefer to line the binding site and to form ligand contacts. An attempt to correlate properties of the unrelated protein-ligand complexes with haem redox potential was made. A compendium of these analyses has been developed and made accessible via the WWW, providing a user-friendly interface for analysing protein-haem interactions. A search tool allows on-the-fly analysis of protein-ligand relationships, which should facilitate both the comparison of different binding sites, and prediction and design of novel ones.

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