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Title: A molecular dynamics study of the vascular endothelial glycocalyx layer
Author: Pikoula, Maria
ISNI:       0000 0004 6499 8658
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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The luminal surface of endothelial cells which line the vasculature is coated with a layer of membrane-bound macromolecules of a mixed carbohydrate and protein nature, collectively described as a glycocalyx, from the greek meaning "sweethusk/covering". Experiments have consistently revealed the pivotal role of the endothelial glycocalyx layer in vasoregulation and the layer's contribution to mechanotransduction pathways. However, the exact mechanism by which the glycocalyx mediates and interprets fluid shear stress remains elusive. This study employsatomic-scale molecular simulation with the aim of investigating the conformational and orientation properties of the highly flexible components of the glycocalyx and their suitability as transduction molecules under hydrodynamic loading. To this aim, two molecular dynamics systems were constructed. The first system focused on the impact of flow on a tethered, branched, oligosaccharide. Fluid flow was shown to only moderately affect the conformation populations explored by the oligosaccharide, in comparison to static conditions. On the other hand, the glycan exhibited a significant orientation change, when compared to simple diffusion, aligning itself with the flow direction. The tethered end of the glycan, an asparagine amino-acid, experienced conformational changes as a result of this flow-induced bias. Results of the "glycan in flow" model suggest that shear flow through the layer can have an impact on the conformational properties of saccharide-decorated transmembrane proteins, thus probably acting as a mechano-transducer. The second system consisted of charged and non-charged heparan sulfate, a component found in large quantities in the endothelial glycocalyx layer. Systems of paired heparan sulfate strands were investigated under conditions of increasing proximity, which is the expected effect of compression of the layer under the effect of flow; a process explored formally using the adaptive biasing force method. This approach warranted the implementation of enhanced sampling for the high energy states of heparan sulfate in close proximity. Results of the heparan sulfate model suggest that areas of locally high charge density within the glycocalyx, generally areas of high sulfation, are characteristically more resistant to compression than non-sulfated areas. The sulfation mix therefore emerges as an important determinant of glycocalyx mechanical properties.
Supervisor: Payne, Steven ; Ventikos, Yiannis Sponsor: RCUK Digital Economy ; Alexander S. Onassis Public Benefit Foundation ; State Scholarships Foundation of Greece (IKY)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available