Mechanisms
Bound phospholipids bend cholesteryl esters into a transferable shape inside CETP, with the N-terminal lipid doing most of the work (J Chem Inf Model 2023)
Original title: Bound Phospholipids Assist Cholesteryl Ester Transfer in the Cholesteryl Ester Transfer Protein
The crystal structure of CETP shows two cholesteryl esters running through its hydrophobic tunnel alongside two phospholipids plugged near the concave surface, but the functional role of these bound phospholipids had not been fully explored beyond earlier animal work ruling out phospholipid transfer itself. Using molecular dynamics, steered molecular dynamics and free energy calculations, this study found the phospholipids transform the unfavourable bent conformation of cholesteryl esters into a favourable linear one, enabling smooth transfer, driven by the making and breaking of contacts between the hydrophobic tunnel residues and the cholesteryl esters in combination with the phospholipids. The N-terminal phospholipid had a more pronounced effect on cholesteryl ester transfer than the C-terminal one, though both were necessary. The authors propose these functionally important phospholipids as a potential target for future cardiovascular drug design, a purely computational structural finding.
Original abstract
Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that assists the transfer of cholesteryl esters (CEs) from antiatherogenic high-density lipoproteins (HDLs) to proatherogenic low-density lipoproteins (LDLs), initiating cholesterol plaques in the arteries. Consequently, inhibiting the activity of CETP is therefore being pursued as a novel strategy to reduce the risk of cardiovascular diseases (CVDs). The crystal structure of CETP has revealed the presence of two CEs running in the hydrophobic tunnel and two plugged-in phospholipids (PLs) near the concave surface. Other than previous animal models that rule out the PL transfer by CETP and PLs in providing the structural stability, the functional importance of bound phospholipids in CETP is not fully explored. Here, we employ a series of molecular dynamics (MD) simulations, steered molecular dynamics (SMD) simulations, and free energy calculations to unravel the effect of PLs on the functionality of the protein. Our results suggest that PLs play an important role in the transfer of neutral lipids by transforming the unfavorable bent conformation of CEs into a favorable linear conformation to facilitate the smooth transfer. The results also suggest that the making and breaking interactions of the hydrophobic tunnel residues with CEs with a combined effort from PLs are responsible for the transfer of CEs. Further, the findings demonstrate that the N-PL has a more pronounced effort on CE transfer than C-PL but efforts from both PLs are essential in the transfer. Thus, we propose that the functionally important PLs can be considered with potential research interest in targeting cardiovascular diseases.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.