Structural and electrostatic flexibility in proteins:-computational approaches to ligand binding

A significant proportion of our understanding of protein-ligand interactions comes about through static pictures, generated through X-ray crystallography. However, in vivo, such interactions occur in a dynamic environment, characterised by flexibility in both the physical , structure, and the electrostatic properties of the molecules involved. Here we assess the importance of such flexibility in the process ofligand binding. Firstly, examining flexibility in ligand confonnation, we apply an algorithmic approach to a representative sample of proteases, and demonstrate that proteases selectively bind ligands in an extended confonnation. Secondly, through the development of a measure ofthe spatial flexibility of residues in a protein structure, we produce a means of predicting the location of ligand binding sites, and, appiying this to the structure of rhodopsin, generate a result that is consistent with recent experimental work on the binding of chlorine to a novel binding site. Finally, we t~rn to a substantial investigation ofthe importance of flexibility in the electronic distribution of a molecule, examining this through a method of modelling molecular mechanics polarisation through atom-centred point charges.EThOS - Electronic Theses Online ServiceGBUnited Kingdo