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

• Main Authors: Artturi Koivuniemi, Timo Vuorela, Petri T Kovanen, Ilpo Vattulainen, Marja T Hyvönen
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2012-01-01
• Series: PLoS Computational Biology
• Online Access: http://europepmc.org/articles/PMC3257282?pdf=render
• ISSN: 1553-734X; 1553-7358

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.