Novel Changes in Discoidal High Density Lipoprotein Morphology: A Molecular Dynamics Study

¹ Departments of Medicine and Biochemistry and Molecular Genetics, University of Alabama at Birmingham
² Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee
³ Center for Computational and Structural Biology, UAB
⁴ Computational Systems Biology Lab, Department of Biochemistry, The University of Georgia, Athens
⁵ School of Biology, Georgia Institute of Technology, Atlanta
⁶ Department of Mathematics, University of Alabama at Birmingham, Alabama

^* To whom correspondence should be addressed. E-mail: segrest{at}uab.edu.

Submitted on July 25, 2005
Revised on August 15, 2005
Accepted on 15 March 2006

	Abstract

ApoA-I is a uniquely flexible lipid-scavenging protein capable of incorporating phospholipid into stable particles. Here we report molecular dynamics (MD) simulations on a series of progressively smaller discoidal high density lipoprotein (HDL) particles produced by incremental removal of palmitoyloleoylphosphatidylcholine (POPC) via four different pathways. The starting model contained 160 POPC and a belt of two antiparallel amphipathic helical lipid-associating domains of apolipoprotein (apo) A-I. The results are particularly compelling. After a few nanoseconds of MD simulation, independent of the starting particle and method of size re-duction, all simulated double belts of the four lipidated apoA-I particles have helical domains that impressively approximate the X-ray crystal structure of lipid-free apoA-I, particularly be-tween residues 88-186. These results provide atomic resolution models for two of the particles produced by in vitro reconstitution of nascent HDL particles. These particles, measuring 95 and 78 Å by nondenaturing gradient gel electrophoresis, correspond in composition and in size/shape (by negative stain electron microscopy) to the simulated particles with molar ratios of 100:2 and 50:2, respectively. The lipids of the 100:2 particle family form minimal surfaces at their monolayer-monolayer interface, while the 50:2 particle family displays a lipid pocket capable of binding a dynamic range of phospholipid molecules.

Key Words: Biophysics of Lipoproteins, Lipid Bilayers, Lipid Metabolism, Molecular Dynamics, Protein Lipid Interactions

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