The class
Molecular dynamics show mixed cholesteryl-ester and triglyceride cargo twists CETP into strained, asymmetric conformations (Phys Chem Chem Phys 2026)
Original title: Beyond the crystal: molecular dynamics investigations of CETP with varied lipid substrates reveal asymmetric dominant motions
A molecular dynamics study examined how CETP behaves when it carries a mixture of cholesteryl esters and triglycerides at once, a heterogeneous condition it encounters physiologically but that prior structural studies had not modelled, having only examined each lipid individually. Compared with the stable, homogeneous cholesteryl-ester-bound state, mixed lipid occupancy caused significant structural instability and expansion, elevated flexibility in lipoprotein-binding loops, and distortion of key secondary structural elements. Large-scale motion analysis showed heterogeneous binding forces CETP into asymmetric, hyper-twisted conformations that disrupt the symmetric bending-twisting motion needed for efficient lipid exchange, with free energy landscapes showing the triglycerides deviating from their normally reported orientation for transfer. The authors argue this conformational strain offers new mechanistic targets for future CETP-directed therapeutics, though the work is purely computational.
Original abstract
Cholesteryl ester transfer protein (CETP) is a crucial therapeutic target for combating cardiovascular disease (CVD) due to its strong influence in modulating high-density lipoprotein (HDL) levels. CETP is responsible for the bidirectional transfer of cholesteryl esters (CEs) and triglycerides (TGs) between different lipoprotein fractions. Although CETP encounters both these neutral lipid substrates when it penetrates deep into lipoprotein cores and can acquire either lipid, prior studies have examined its conformational space only in the presence of CEs or TGs individually. Here, we investigate the uncharacterised dynamics of CETP in heterogeneous lipid environments (CE-TG and TG-CE) using molecular dynamics simulations. Compared to the stable, homogeneous CE-bound state, the introduction of TG, particularly in mixed CE/TG configurations, induces significant structural instability and protein expansion. Mixed-lipid occupancy leads to elevated flexibility in critical lipoprotein-binding loops and the distortion of vital secondary structural elements. Furthermore, large-scale collective motion analyses reveal that heterogeneous binding forces CETP into aberrant, asymmetric, and hyper-twisted conformations. This disrupts the symmetric bending-twisting balance essential for efficient lipid exchange. Free energy landscapes confirm that the TGs within the mixed-lipid systems exhibit varied conformational states and adopt orientations that deviate from their reported parallel N-N orientation for lipid transfer through CETP. These findings suggest that the simultaneous presence of CE and TG imposes considerable conformational strain, fundamentally impairing CETP's lipid transport mechanism and offering novel mechanistic insights for future CETP-targeted therapeutics.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.