Structure, Assembly, and Maturation of High -Density Lipoproteins

High-density lipoproteins (HDL) are protein-lipid particles that are involved in the transport of cholesterol in the blood. They are of great importance in the treatment of coronary heart disease as low levels of HDLs are a known risk factor for the development of arteriosclerosis. Little is known about the molecular level structure of these HDL particles or the mechanism by which they assemble from lipid-free proteins into discoidal protein-lipid particles and then into spherical particles. This thesis presents molecular dynamics simulations with comparisons to experimental small-angle X-ray scattering results which begin to characterize the initial stages of HDL biogenesis. Starting from all-atom simulations done to characterize the double-belt structure of discoidal HDL particles. Then moving on to the development and subsequent refinement of a coarse-grained protein-lipid model developed to allow for long timescale simulations of lipoproteins. The coarse-grained model is validated through comparisons with small-angle X-ray scattering measurements and by reverse coarse-graining methods. Self-assembly simulations of discoidal HDL particles were performed which showed the initial aggregation of proteins and lipids are driven by the hydrophobic effect. This is followed by a slower protein tertiary structure rearrangement which eventually results in the formation of a double-belt model discoidal HDL particle. The conversion of discoidal HDL into spherical HDL particles is investigated through the stepwise addition of cholesterol esters into an HDL particle using coarse-grained molecular dynamics. This process shows the dynamic formation of a hydrophobic cholesterol ester core which leads to change in the global particle shape. Reverse coarse-graining of the final spherical HDL particle, allows for the generation of a detailed atomic level image of a spherical HDL. Additionally, insights into how nanodiscs, a reconstituted discoidal HDL mimic, used as platforms for embedding and studying membrane proteins, are self-assembled or disassembled due to the presence of cholate molecules are presented.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2015

Author dc:creator

• Shih, Amy

Contributors dc:contributor

• Schulten, Klaus J.
• Sligar, Stephen G.

• Biophysics, General

Language dc:language

eng

Identifier

(MiAaPQ)AAI3314893

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/87912