Structure of spheroidal HDL particles revealed by combined atomistic and coarse grained simulations

¹ Tampere University of Technology
² University of Alabama at Birmingham
³ North Carolina State University
⁴ University of Groningen
⁵ Helsinki University of Technology
⁶ The University of Western Ontario
⁷ Tampere University of Technology and Helsinki University of Technology

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

Submitted on August 3, 2007
Revised on August 30, 2007
Accepted on 5 November 2007

	Abstract

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 have 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 have studied. The observed small contribution of cholesteryl oleate (CO) molecules to the solvent accessible surface area of the entire ms-HDL particle indicates that palmitoyloleoylphosphatidylcholines (POPC) and apoA-I molecules cover particularly well the hydrophobic core comprised of cholesteryl esters. 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. The interaction of annular CO molecules is proposed to contribute to apoA-I rigidity stabilizing and regulating the structure and function of the ms-HDL particle.

Key Words: Cholesteryl esters, HDL, Lipoproteins, Molecular Dynamics

This article has been cited by other articles:

				M. J. Thomas, S. Bhat, and M. G. Sorci-Thomas Three-dimensional models of HDL apoA-I: implications for its assembly and function J. Lipid Res., September 1, 2008; 49(9): 1875 - 1883. [Abstract] [Full Text] [PDF]

				R. A. G. D. Silva, R. Huang, J. Morris, J. Fang, E. O. Gracheva, G. Ren, A. Kontush, W. G. Jerome, K.-A. Rye, and W. S. Davidson Structure of apolipoprotein A-I in spherical high density lipoproteins of different sizes PNAS, August 26, 2008; 105(34): 12176 - 12181. [Abstract] [Full Text] [PDF]