PLoS Computational Biology (Jan 2012)

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

  • Artturi Koivuniemi,
  • Timo Vuorela,
  • Petri T Kovanen,
  • Ilpo Vattulainen,
  • Marja T Hyvönen

DOI
https://doi.org/10.1371/journal.pcbi.1002299
Journal volume & issue
Vol. 8, no. 1
p. e1002299

Abstract

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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.