Mechanisms
Existing CETP inhibitors were designed against an unglycosylated crystal structure, but simulations show four sugar chains reshape the tunnel dynamics of the protein (Proteins 2018)
Original title: Role of glycans in cholesteryl ester transfer protein revealed by molecular dynamics simulation
Current CETP inhibitors were designed based on the unglycosylated crystal structure of the protein, yet most have failed to translate into approved cardiovascular drugs, prompting this study to examine how glycosylation affects CETP structure and function. Using 3.0 microsecond molecular dynamics trajectories comparing the nascent (unglycosylated) and glycosylated forms of CETP, the glycosylated form adopted a more stretched shape with larger, more variable solvent-accessible surface area at the N-terminus, where Glycan88 partially assists cholesteryl ester movement. Glycan341 reduced flexibility of the neck flap and interfered with cholesteryl ester passage through the neck region, Glycan240 reduced flexibility of Helix-X to similarly interfere with transfer, and Glycan396 reduced C-terminal flexibility while increasing its hydrophobic surface area. These effects arose from glycans forming hydrogen bonds with surrounding residues, with reciprocal influence from those residues on glycan conformation. The authors argue glycans are an integral part of CETP structure and function, and that future inhibitor design and CVD treatment research should account for them, a purely computational structural finding.
Original abstract
Current cholesteryl ester transfer protein (CETP) inhibitors are designed based on the unglycosylated crystal structure, and most of them have failed to cure cardiovascular disease (CVD). It is particularly important for us to investigate the glycosylation structure of CETP (CETP-G) and effect of glycans on the structure and function of CETP. Here, we used a total of 3.0-μs molecular dynamics (MD) trajectories of nascent structure of CETP (CETP-N) and CETP-G to study their structural differentiations, to shed new light on the CETP-mediated lipid exchange. In accordance with our simulations and previous mutation studies, relative to CETP-N, CETP-G adopts a more stretched shape with higher hydrophobic and hydrophilic solvent-accessible surface area (SASA) of N-terminal oscillating with larger amplitude, in which Glycan88 provides partial assistance for CEs through the N-terminal. Glycan341 reduces the flexibility of neck flap, with the interference of CEs through the neck region. Besides, Glycan240 reduces the flexibility of Helix-X to interfere the CEs transfer. Glycan396 decreases the flexibility and increases the hydrophobic SASA of C-terminal. Overall, these glycans affect the dynamics and structure of CETP through forming H-bonds with surrounding residues, and the sampled conformations of glycan is also affected by its surrounding residues. Thus, glycans are an integral part of CETP, further studies on the CETP inhibition and treatment of CVD should fully consider the effect of glycans.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.