Abstract
Cholesteryl ester transfer protein (CETP) mediates the reciprocal transfer of neutral lipids (cholesteryl esters, triglycerides) and phospholipids between different lipoprotein fractions in human blood plasma. A novel molecular agent known as anacetrapib has been shown to inhibit CETP activity and thereby raise high density lipoprotein (HDL)-cholesterol and decrease low density lipoprotein (LDL)-cholesterol, thus rendering CETP inhibition an attractive target to prevent and treat the development of various cardiovascular diseases. Our objective in this work is to use atomistic molecular dynamics simulations to shed light on the inhibitory mechanism of anacetrapib and unlock the interactions between the drug and CETP. The results show an evident affinity of anacetrapib towards the concave surface of CETP, and especially towards the region of the N-terminal tunnel opening. The primary binding site of anacetrapib turns out to reside in the tunnel inside CETP, near the residues surrounding the N-terminal opening. Free energy calculations show that when anacetrapib resides in this area, it hinders the ability of cholesteryl ester to diffuse out from CETP. The simulations further bring out the ability of anacetrapib to regulate the structure-function relationships of phospholipids and helix X, the latter representing the structural region of CETP important to the process of neutral lipid exchange with lipoproteins. Altogether, the simulations propose CETP inhibition to be realized when anacetrapib is transferred into the lipid binding pocket. The novel insight gained in this study has potential use in the development of new molecular agents capable of preventing the progression of cardiovascular diseases.
Highlights
Cholesteryl ester transfer protein (CETP) is a 476-residue-long hydrophobic glycoprotein that transports cholesteryl esters (CEs), triglycerides, and phospholipids between high density lipoprotein (HDL) and other lipoprotein fractions in human blood plasma [1]
The inherent curvature of CETP matches well with the curvature of HDL particles that may result from the fact that a major part of CETP has been shown to be associated with HDL due to higher binding affinity compared with plasma low density lipoproteins (LDL) or very low density lipoproteins (VLDL) [1]
One of the most encouraging treatment methods to prevent the generation and progression of cardiovascular disease is the elevation of high density lipoprotein (HDL) levels in circulation, as high HDL levels have been found to correlate negatively with the risk of cardiovascular disease
Summary
Cholesteryl ester transfer protein (CETP) is a 476-residue-long hydrophobic glycoprotein that transports cholesteryl esters (CEs), triglycerides, and phospholipids between high density lipoprotein (HDL) and other lipoprotein fractions in human blood plasma [1]. CETP attaches to the surface of a lipoprotein via its concave surface where the two tunnel openings reside [2,4]. The openings are expected to serve as passages to the flow of neutral lipids (CEs and triglycerides) between the particles, and their location supports the view that the concave surface is the only site able to bind lipoproteins, since other surfaces of the protein lack direct access to the tunnel. In a recent molecular dynamics simulation study it was shown that after the attachment of CETP to lipoprotein surface, helix X is able to fold into the hydrophobic tunnel and interact with the CETP-bound CE [4]. After the lipids have been exchanged, the tunnel openings are plugged by phospholipids followed by the detachment of CETP from the lipoprotein surface.
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