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The role of water molecules in biomolecular interfaces

Henriques, Denise Aguiar; (2000) The role of water molecules in biomolecular interfaces. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Whilst the incorporation of water occurs in many biomolecular interfaces, the role they play is poorly understood with little attention paid to their contribution in dictating the specificity of an interaction. To investigate this the Src Homology 2 (SH2) domain of the viral Src protein kinase and its interactions with various phosphotyrosyl peptides and peptidomimetic ligands was studied. X-ray analysis shows that a feature of SH2 domains is the involvement of water molecules in the peptide binding-site. SH2 domains play a fundamental role in signal transduction and are therapeutic drug targets. Changes in water molecule content (incorporation, removal) and/or effects on binding affinity of the biomolecular complexes are examined using a combination of the thermodynamic isothermal titration calorimetry (ITC) and nanoflow electrospray ionisation mass spectrometry (ESI-MS) techniques and correlated to known structural information. The results from this study are used to predict the nature of possible water-mediated binding in the SH2 domain of Fyn using similar ligands. The role of water in binding interactions is further investigated by applying an empirical relationship based on the correlation of solvent-accessible surface area burial and changes in heat capacity (ΔCp). The experimental ΔCp is determined using ITC for the SH2/ligand interactions. The effects of proton linkage on binding are considered and five different surface area-based models are tested (relating to the treatment of conformational flexibility in the peptide ligand and the inclusion of proximal ordered solvent molecules in the surface area calculations). This allows the calculation of a range of thermodynamic state functions (ΔCp, ΔS, ΔH and ΔG) directly from structure. Comparison with the experimentally derived data shows little agreement for the observed trends in the interactions of selected phosphotyrosyl peptides and SrcSH2. Furthermore, the different models have a dramatic effect on the calculated thermodynamic functions, thus binding energies predicted from these types of correlations are highly model dependent.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The role of water molecules in biomolecular interfaces
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Pure sciences; Water molecules
URI: https://discovery.ucl.ac.uk/id/eprint/10103026
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