Insights into the Tunnel Mechanism of Cholesteryl Ester Transfer Protein through All-atom Molecular Dynamics Simulations

Cholesteryl ester transfer protein (CETP) mediates cholesteryl ester (CE) transfer from the atheroprotective high density lipoprotein (HDL) cholesterol to the atherogenic low density lipoprotein cholesterol. In the past decade, this property has driven the development of CETP inhibitors, which have...

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Bibliographic Details
Published in:The Journal of biological chemistry 2016-07, Vol.291 (27), p.14034-14044
Main Authors: Lei, Dongsheng, Rames, Matthew, Zhang, Xing, Zhang, Lei, Zhang, Shengli, Ren, Gang
Format: Article
Language:English
Subjects:
BASIC BIOLOGICAL SCIENCES
cholesterol
Cholesterol Ester Transfer Proteins - chemistry
Cholesterol Ester Transfer Proteins - metabolism
Cholesterol Esters - metabolism
cholesterol metabolism
cholesterol regulation
cholesterol-binding protein
Computational Biology
Humans
lipid metabolism
lipid transport
lipid-protein interaction
lipoprotein metabolism
Microscopy, Electron
molecular dynamics
Molecular Dynamics Simulation
Protein Conformation
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Summary:Cholesteryl ester transfer protein (CETP) mediates cholesteryl ester (CE) transfer from the atheroprotective high density lipoprotein (HDL) cholesterol to the atherogenic low density lipoprotein cholesterol. In the past decade, this property has driven the development of CETP inhibitors, which have been evaluated in large scale clinical trials for treating cardiovascular diseases. Despite the pharmacological interest, little is known about the fundamental mechanism of CETP in CE transfer. Recent electron microscopy (EM) experiments have suggested a tunnel mechanism, and molecular dynamics simulations have shown that the flexible N-terminal distal end of CETP penetrates into the HDL surface and takes up a CE molecule through an open pore. However, it is not known whether a CE molecule can completely transfer through an entire CETP molecule. Here, we used all-atom molecular dynamics simulations to evaluate this possibility. The results showed that a hydrophobic tunnel inside CETP is sufficient to allow a CE molecule to completely transfer through the entire CETP within a predicted transfer time and at a rate comparable with those obtained through physiological measurements. Analyses of the detailed interactions revealed several residues that might be critical for CETP function, which may provide important clues for the effective development of CETP inhibitors and treatment of cardiovascular diseases.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M116.715565