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Title: Investigating the interaction of the PKB PH domain with inositol phosphate-based compounds
Author: Rosen, Sarah Ann Jacqueline
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Protein kinase B (PKB) plays a key role in the phosphoinositide 3-kinase pathway, one of the most frequently activated proliferation pathways in cancer. A key stage in this pathway is PKB's translocation to the plasma membrane, which is driven by direct interaction of PKB's pleckstrin homology (PH) domain with the inositol phosphate head-groups of phosphoinositide lipids PtdIns(3,4,5)P3 and PtdIns(3,4)P2. In this thesis a computational approach has been applied to study the interaction between PKB's PH domain and the inositol phosphate head-groups of phosphoinositide lipids. Herein the first full set of parameters for these inositol phosphates has been generated using a clearly defined algorithmic approach. The parameters have been applied in a total of 6 μs of molecular dynamics (MD) simulations to investigate the interaction between inositol phosphates and the PKB PH domain. The simulations successfully mirror, and additionally rationalise, PKB's experimental interactions and behaviour. As well as investigating the native system, a PKB mutant that has been reported in multiple human cancers has also been explored. This PKB mutant constitutively targets the plasma membrane due to its broadened phosphoinositide selectivity. The atomic-level view available from MD simulations has helped elucidate the molecular mechanism behind this. Information obtained about the PKB PH domain's binding interface has been used to design inositol phosphate derivatives to inhibit PKB activation. MD simulations have allowed a number of inositol phosphate derivatives to be rapidly screened for their inhibitory behaviour. The predicted behaviour of a select number of these derivatives has been further assessed using biochemical techniques. Gratifyingly, the computational and biochemical results are shown to be in good agreement.
Supervisor: Gould, Ian ; Mann, David Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available