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

Andrea Catte ^*, James C. Patterson ^*, Martin K. Jones ^*, W. Gray Jerome , Denys Bashtovyy ^*, Zhengchang Su , Feifei Gu ^*, Jianguo Chen ^*, Marcela P. Aliste ^¶, Stephen C. Harvey ^¶, Ling Li ^*, Gilbert Weinstein  and Jere P. Segrest ^*

^* Departments of Medicine and Biochemistry and Molecular Genetics, and Center for Computational and Structural Biology, and Department of Mathematics, University of Alabama at Birmingham, Birmingham, Alabama 35294; Computational Systems Biology Lab, Department of Biochemistry & Molecular Biology, The University of Georgia, Athens, Georgia 30602; Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232; and ^¶ School of Biology, Georgia Institute of Technology, Atlanta, Georgia 30332

Correspondence: Address reprint requests to Jere P. Segrest, 1808 7th Ave. S., Boshell Diabetes Building 630, Depts. of Medicine and Biochemistry and Molecular Genetics, and Center for Computational and Structural Biology, Birmingham, AL 35294. Tel.: 205-934-4420; Fax: 205-975-8070; E-mail: segrest{at}uab.edu.

ApoA-I is a uniquely flexible lipid-scavenging protein capable of incorporating phospholipids into stable particles. Here we report molecular dynamics simulations on a series of progressively smaller discoidal high density lipoprotein particles produced by incremental removal of palmitoyloleoylphosphatidylcholine via four different pathways. The starting model contained 160 palmitoyloleoylphosphatidylcholines 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 molecular dynamics simulation, independent of the starting particle and method of size reduction, 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 between residues 88 and 186. These results provide atomic resolution models for two of the particles produced by in vitro reconstitution of nascent high density lipoprotein particles. These particles, measuring 95 Å 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, whereas the 50:2 particle family displays a lipid pocket capable of binding a dynamic range of phospholipid molecules.

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