Lipid exchange mechanism of the cholesteryl ester transfer protein clarified by atomistic and coarse-grained simulations

Artturi Koivuniemi (Corresponding Author), Timo Vuorela, Petri T. Kovanen, Ilpo Vattulainen, Marja T. Hyvönen

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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.
Original languageEnglish
Article numbere1002299
Number of pages9
JournalPLoS Computational Biology
Volume8
Issue number1
DOIs
Publication statusPublished - 2012
MoE publication typeA1 Journal article-refereed

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cholesteryl ester transfer protein
Cholesterol Ester Transfer Proteins
Lipids
ester
Esters
lipid
Proteins
Protein
protein
lipids
simulation
Simulation
cholesteryl esters
Cholesterol Esters
Helix
Droplet
droplets
Lipoproteins
Phospholipids
droplet

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Koivuniemi, Artturi ; Vuorela, Timo ; Kovanen, Petri T. ; Vattulainen, Ilpo ; Hyvönen, Marja T. / Lipid exchange mechanism of the cholesteryl ester transfer protein clarified by atomistic and coarse-grained simulations. In: PLoS Computational Biology. 2012 ; Vol. 8, No. 1.
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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.",
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Lipid exchange mechanism of the cholesteryl ester transfer protein clarified by atomistic and coarse-grained simulations. / Koivuniemi, Artturi (Corresponding Author); Vuorela, Timo; Kovanen, Petri T.; Vattulainen, Ilpo; Hyvönen, Marja T.

In: PLoS Computational Biology, Vol. 8, No. 1, e1002299, 2012.

Research output: Contribution to journalArticleScientificpeer-review

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AB - 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.

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