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Structure of Spheroidal HDL Particles Revealed by Combined Atomistic and Coarse-Grained Simulations

Andrea Catte ^* , James C. Patterson ^*, Denys Bashtovyy ^*, Martin K. Jones ^*, Feifei Gu ^*, Ling Li ^*, Aldo Rampioni , Durba Sengupta , Timo Vuorela , Perttu Niemelä , Mikko Karttunen ^¶, Siewert Jan Marrink , Ilpo Vattulainen   ^|| and Jere P. Segrest ^*

^* Department of Medicine and Center for Computational and Structural Biology, University of Alabama at Birmingham, Birmingham, Alabama; Institute of Physics, Tampere University of Technology, Tampere, Finland; Molecular Dynamics Group, Groningen Biomolecular Sciences and Biotechnology Institute, Department of Biophysical Chemistry, University of Groningen, Groningen, The Netherlands; Laboratory of Physics and Helsinki Institute of Physics, Helsinki University of Technology, Helsinki, Finland; ^¶ Department of Applied Mathematics, The University of Western Ontario, London, Ontario, Canada; and ^|| MEMPHYS Center for Biomembrane Physics, University of Southern Denmark, Odense, Denmark

Correspondence: Address reprint requests to Jere P. Segrest, 1808 7th Ave. S, Boshell Diabetes Building 630, Depts. of Medicine, 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.

Spheroidal high-density lipoprotein (HDL) particles circulating in the blood are formed through an enzymatic process activated by apoA-I, leading to the esterification of cholesterol, which creates a hydrophobic core of cholesteryl ester molecules in the middle of the discoidal phospholipid bilayer. In this study, we investigated the conformation of apoA-I in model spheroidal HDL (ms-HDL) particles using both atomistic and coarse-grained molecular dynamics simulations, which are found to provide consistent results for all HDL properties we studied. The observed small contribution of cholesteryl oleate molecules to the solvent-accessible surface area of the entire ms-HDL particle indicates that palmitoyloleoylphosphatidylcholines and apoA-I molecules cover the hydrophobic core comprised of cholesteryl esters particularly well. The ms-HDL particles are found to form a prolate ellipsoidal shape, with sizes consistent with experimental results. Large rigid domains and low mobility of the protein are seen in all the simulations. Additionally, the average number of contacts of cholesteryl ester molecules with apoA-I residues indicates that cholesteryl esters interact with protein residues mainly through their cholesterol moiety. We propose that the interaction of annular cholesteryl oleate molecules contributes to apoA-I rigidity stabilizing and regulating the structure and function of the ms-HDL particle.