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Title: In silico modelling of membranes and drug membrane interactions
Author: Dickson, Callum
ISNI:       0000 0004 5348 9495
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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A new all-atom force field for the simulation of phospholipid bilayers using the AMBER molecular dynamics package has been developed, which is compatible with other AMBER protein, nucleic acid, carbohydrate and small molecule force fields. The force field has been validated by simulating bilayers of six different lipid types, finding favourable comparison to experiment for properties such as area per lipid, volume per lipid, bilayer thickness, NMR order parameters, scattering data, and lipid lateral diffusion. The modular nature of this force field allows numerous combinations of head and tail groups to create different lipid types, enabling the easy insertion of new lipid species. The lipid bilayer model has then been applied to the study of the interaction between radioimaging agents and membranes in an effort to understand the phenomena of non-specific binding, which remains poorly understood yet of serious detrimental consequence to the development of new imaging tracers. The effect of different concentrations of imaging agent on a homogeneous membrane has been examined using unbiased simulations, whilst the permeability coefficient of each imaging agent through a membrane has been calculated using biased simulations. It is found that radiotracers with low non-specific binding must adopt a certain orientation to cross the head group region of a membrane - this requirement may act as a barrier to membrane entry. Furthermore, once partitioned into the membrane, simulations predict that those radiotracers displaying a high degree of non-specific binding act to order lipid tail groups to a greater extent than those with low non-specific binding, reducing the permeability of the membrane and possibly acting to 'trap' radiotracer in the membrane. These simulations also predict that non-specific binding is not related to radiotracer membrane permeability through a homogeneous bilayer.
Supervisor: Gould, Ian Sponsor: Biotechnology and Biological Sciences Research Council ; GlaxoSmithKline
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral