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Title: 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 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 inhibitorsmore » and treatment of cardiovascular diseases.« less
Authors:
 [1] ;  [2] ;  [1] ;  [3] ;  [3] ;  [2]
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Xi'an Jiaotong Univ. (China)
  2. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  3. Xi'an Jiaotong Univ. (China)
Publication Date:
Grant/Contract Number:
AC02-05CH11231; 1R01HL115153; 11074196; 11374237
Type:
Accepted Manuscript
Journal Name:
Journal of Biological Chemistry
Additional Journal Information:
Journal Volume: 291; Journal Issue: 27; Journal ID: ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular Biology
Research Org:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Xi'an Jiaotong Univ. (China)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Inst. of Health (NIH) (United States); National Natural Science Foundation of China (NNSFC)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; cholesterol; cholesterol metabolism; cholesterol regulation; cholesterol-binding protein; lipid metabolism; lipid transport; lipid-protein interaction; lipoprotein metabolism; molecular dynamics
OSTI Identifier:
1379410

Lei, Dongsheng, Rames, Matthew, Zhang, Xing, Zhang, Lei, Zhang, Shengli, and Ren, Gang. Insights into the Tunnel Mechanism of Cholesteryl Ester Transfer Protein through All-atom Molecular Dynamics Simulations. United States: N. p., Web. doi:10.1074/jbc.M116.715565.
Lei, Dongsheng, Rames, Matthew, Zhang, Xing, Zhang, Lei, Zhang, Shengli, & Ren, Gang. Insights into the Tunnel Mechanism of Cholesteryl Ester Transfer Protein through All-atom Molecular Dynamics Simulations. United States. doi:10.1074/jbc.M116.715565.
Lei, Dongsheng, Rames, Matthew, Zhang, Xing, Zhang, Lei, Zhang, Shengli, and Ren, Gang. 2016. "Insights into the Tunnel Mechanism of Cholesteryl Ester Transfer Protein through All-atom Molecular Dynamics Simulations". United States. doi:10.1074/jbc.M116.715565. https://www.osti.gov/servlets/purl/1379410.
@article{osti_1379410,
title = {Insights into the Tunnel Mechanism of Cholesteryl Ester Transfer Protein through All-atom Molecular Dynamics Simulations},
author = {Lei, Dongsheng and Rames, Matthew and Zhang, Xing and Zhang, Lei and Zhang, Shengli and Ren, Gang},
abstractNote = {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.},
doi = {10.1074/jbc.M116.715565},
journal = {Journal of Biological Chemistry},
number = 27,
volume = 291,
place = {United States},
year = {2016},
month = {5}
}

Works referenced in this record:

A simple method for displaying the hydropathic character of a protein
journal, May 1982