Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.557387
Title: Dynamics and thermodynamics of protein-ligand interactions
Author: Malham, Richard William
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2012
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Abstract:
Complex networks of protein-ligand interactions underpin cellular function and communication. Disease can arise from disruption of these networks through the alteration of protein-ligand interaction affinities, for example by protein mutation or ligand modification. Understanding the mechanisms and principles that define affinity is therefore critical to both understanding and engineering biomolecular interactions, e.g. optimising drug molecules to interact effectively with their biomolecular targets. Thermodynamics reveals that affinity can be expressed in terms of the Gibbs free energy change upon interaction. In turn, this is composed of enthalpic and entropic terms, which can be thought of loosely as arising from structural and dynamic factors respectively. Though enthalpic terms can be estimated to a reasonable degree using structural data, a better understanding of entropic contributions from dynamic processes is required. The mouse major urinary protein (MUP) has been successfully established as a model system to investigate the thermodynamics of protein-ligand interactions. This work uses MUP, and employs a wide range of biophysical techniques, to develop our understanding of the dynamic factors in the thermodynamics of protein-ligand interactions. Four factors are addressed. Protein solvation is addressed by investigating proposed entropic solvation of the MUP binding pocket, and the possibility of engineering a new binding profile through manipulation of sidechains and solvation in the binding pocket. Ligand conformational entropy is addressed by performing the first systematic assessment of the widely predicted, yet inconsistently observed, benefits of removing and restricting ligand bonds. The greatest entropic loss upon binding, that of ligand rotational and translational entropy, is addressed by assessing MD predictions of significant residual translation and rotational motion of IBMP bound to MUP. This is achieved by using a combination of NMR techniques. Finally, protein dynamics are addressed by undertaking a preliminary investigation of a potentially promising novel technique for probing site-specific changes in protein dynamics upon ligand binding.
Supervisor: Homans, S. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.557387  DOI: Not available
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