title: Lipid exchange mechanism of the cholesteryl ester transfer protein clarified by atomistic and coarse-grained simulations.
abstract: Cholesteryl ester transfer protein (CETP) transports cholesteryl esters, triglycerides, and phospholipids between different lipoprotein fractions in blood plasma. The inhibition of CETP has been shown to be a sound strategy to prevent and treat the development of coronary heart disease. We employed molecular dynamics simulations to unravel the mechanisms associated with the CETP-mediated lipid exchange. To this end we used both atomistic and coarse-grained models whose results were consistent with each other. We found CETP to bind to the surface of high density lipoprotein (HDL) -like lipid droplets through its charged and tryptophan residues. Upon binding, CETP rapidly (in about 10 ns) induced the formation of a small hydrophobic patch to the phospholipid surface of the droplet, opening a route from the core of the lipid droplet to the binding pocket of CETP. This was followed by a conformational change of helix X of CETP to an open state, in which we found the accessibility of cholesteryl esters to the C-terminal tunnel opening of CETP to increase. Furthermore, in the absence of helix X, cholesteryl esters rapidly diffused into CETP through the C-terminal opening. The results provide compelling evidence that helix X acts as a lid which conducts lipid exchange by alternating the open and closed states. The findings have potential for the design of novel molecular agents to inhibit the activity of CETP.
authors.affiliation: Department of Physics, Tampere University of Technology, Tampere, Finland. artturi.koivuniemi@vtt.fi
authors.forename: Artturi
authors.initials: A
authors.lastname: Koivuniemi
authors.forename: Timo
authors.initials: T
authors.lastname: Vuorela
authors.forename: Petri T
authors.initials: PT
authors.lastname: Kovanen
authors.forename: Ilpo
authors.initials: I
authors.lastname: Vattulainen
authors.forename: Marja T
authors.initials: MT
authors.lastname: Hyvönen
mesh_terms: D001665:Binding Sites; D053480:Cholesterol Ester Transfer Proteins / Q000737:chemistry* / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism; D003198:Computer Simulation; D008075:Lipoproteins, HDL / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D011487:Protein Conformation
chemical_list: D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D008075:Lipoproteins, HDL