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Title: Positively cooperative binding and the tightening of non-covalent bonds
Author: Davies, N. L.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2004
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Molecular recognition is addressed in the present work, with particular reference to the vancomycin family of antibiotics and the phenomenon of cooperativity between ligand binding and dimerisation. These relatively small molecules can be used as model receptors in which single binding interactions, or non-covalent interfaces, can be studied by 1H NMR spectroscopy. Chapter 2 investigates the relative affinities, and effect on antibiotic dimerisation, of a series of ligands based on benzoyl-Gly-Gly to ristocetin A. In Chapter 3, an alternative model to account for increased downfield chemical shift changes of a proton as the number of ligand/antibiotic interactions is increased is discussed. The new model proposes a reduction in the population of partially bound states, as opposed to structural tightening to account for the chemical shift data. Determination of the protection factors of the amide protons involved in hydrogen bonding clearly excludes this model, and establishes that adjacent binding interactions serve to strengthen existing hydrogen bonds. Binding of indole-2-carboxylic acid to chloroeremomycin is investigated in Chapter 4. The ligand/chloroeremomycin dimer interactions are shown to occur with positive cooperativity and structural tightening. Finally, in Chapter 5 it is resolved that ligand binding is positively cooperative with respect to the ristocetin A dimer, contrary to changes in the relative populations of the monomer and dimer species. Strong hydrogen bonds formed in the binding sites of the ligands are reinforced in the dimer relative to the monomer, and the barrier to dissociation of the dimer is increased upon ligand binding.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available