TCB Publications - Abstract

Amy Y. Shih, Stephen G. Sligar, and Klaus Schulten. Maturation of high-density lipoproteins. Journal of the Royal Society Interface, 6:863-871, 2009. (PMC: 2805102)

SHIH2009 Human high-density lipoproteins (HDL) are involved in the transport of lipids and cholesterol through the blood stream protecting people from vascular diseases. The mechanism by which HDL functions is not well understood due to a lack of structural information, in particular of the mature circulating spherical HDL particles. Here we report an atomic level view of spherical HDL furnished through molecular dynamics simulations. An intermediate form, discoidal HDL, had been characterized through experimental observations and computational modeling involving coarse-grained and all-atom molecular dynamics. Discoidal HDL is typically composed of two belt-like apolipoprotein A-I strands encircling a lipid bilayer. We have extend the prior computational modeling to investigate the maturation of discoidal HDL to spherical HDL which contains numerous molecules of cholesterol ester. Sixty cholesterol ester molecules were added in a stepwise fashion in order to mimic how HDL particles naturally mature. The resulting matured particle, captured first in a coarse-grained description, was then described in a consistent all-atom representation and analyzed in chemical detail. The simulations show that HDL maturation results from the formation of a hydrophobic core comprised of cholesterol ester molecules surrounded by phospholipid and protein; the two apolipoprotein strands remain in a belt-like conformation with flexible N- and C-terminal helices and a stable central region (helices 3 to 7) stabilized by salt-bridges. The central region binds with and activates the enzyme lectithin cholesterol acyl transferase that converts cholesterol into cholesterol ester for incorporation into HDL.

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