title: Insights into the Tunnel Mechanism of Cholesteryl Ester Transfer Protein through All-atom Molecular Dynamics Simulations.
abstract: 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.
authors.affiliation: The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, California 94720; Department of Applied Physics, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Lei
authors.affiliation: The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, California 94720.
authors.forename: Matthew
authors.initials: M
authors.lastname: Rames
authors.affiliation: The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, California 94720; Department of Applied Physics, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Applied Physics, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Applied Physics, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China. Electronic address: zhangsl@xjtu.edu.cn.
authors.forename: Shengli
authors.initials: S
authors.lastname: Zhang
authors.affiliation: The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, California 94720. Electronic address: gren@lbl.gov.
authors.forename: Gang
authors.initials: G
authors.lastname: Ren
mesh_terms: D053480:Cholesterol Ester Transfer Proteins / Q000737:chemistry* / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism; D006801:Humans; D008854:Microscopy, Electron; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation
chemical_list: C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters
keywords: cholesterol; cholesterol metabolism; cholesterol regulation; cholesterol-binding protein; lipid metabolism; lipid transport; lipid-protein interaction; lipoprotein metabolism; molecular dynamics