title: Structures of discoidal high density lipoproteins: a combined computational-experimental approach.
abstract: Conversion of discoidal phospholipid (PL)-rich high density lipoprotein (HDL) to spheroidal cholesteryl ester-rich HDL is a central step in reverse cholesterol transport. A detailed understanding of this process and the atheroprotective role of apolipoprotein A-I (apoA-I) requires knowledge of the structure and dynamics of these various particles. This study, combining computation with experimentation, illuminates structural features of apoA-I allowing it to incorporate varying amounts of PL. Molecular dynamics simulated annealing of PL-rich HDL models containing unesterified cholesterol results in double belt structures with the same general saddle-shaped conformation of both our previous molecular dynamics simulations at 310 K and the x-ray structure of lipid-free apoA-I. Conversion from a discoidal to a saddle-shaped particle involves loss of helicity and formation of loops in opposing antiparallel parts of the double belt. During surface expansion caused by the temperature-jump step, the curved palmitoyloleoylphosphatidylcholine bilayer surfaces approach planarity. Relaxation back into saddle-shaped structures after cool down and equilibration further supports the saddle-shaped particle model. Our kinetic analyses of reconstituted particles demonstrate that PL-rich particles exist in discrete sizes corresponding to local energetic minima. Agreement of experimental and computational determinations of particle size/shape and apoA-I helicity provide additional support for the saddle-shaped particle model. Truncation experiments combined with simulations suggest that the N-terminal proline-rich domain of apoA-I influences the stability of PL-rich HDL particles. We propose that apoA-I incorporates increasing PL in the form of minimal surface bilayers through the incremental unwinding of an initially twisted saddle-shaped apoA-I double belt structure.
authors: Department of Medicine and Atherosclerosis Research Unit, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors: Feifei
authors: F
authors: Gu
authors: Martin K
authors: MK
authors: Jones
authors: Jianguo
authors: J
authors: Chen
authors: James C
authors: JC
authors: Patterson
authors: Andrea
authors: A
authors: Catte
authors: W Gray
authors: WG
authors: Jerome
authors: Ling
authors: L
authors: Li
authors: Jere P
authors: JP
authors: Segrest
mesh_terms: D016632:Apolipoprotein A-I / Q000737:chemistry / Q000378:metabolism; D002942:Circular Dichroism; D019295:Computational Biology; D006801:Humans; D008074:Lipoproteins / Q000737:chemistry* / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000737:chemistry* / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009154:Mutation; D010713:Phosphatidylcholines / Q000737:chemistry
chemical_list: D016632:Apolipoprotein A-I; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D010713:Phosphatidylcholines; C034366:discoidal lipoproteins; C028694:1-palmitoyl-2-oleoylphosphatidylcholine