HDL biology
Atomistic simulations reveal how CETP penetrates HDL via a tryptophan anchor and phenylalanine barrier (J Lipid Res 2015)
Original title: Atomistic MD simulation reveals the mechanism by which CETP penetrates into HDL enabling lipid transfer from HDL to CETP
To better understand CETP-HDL interaction at the atomic level, researchers built an HDL particle mimicking actual human HDL mass composition and ran large-scale atomistic molecular dynamics simulations of an upright CETP interacting with it, the first such simulation of its kind. The results showed CETP can penetrate the HDL particle surface, forming an opening at the N-barrel domain end of CETP, with a tryptophan-rich region of this domain serving as the major anchoring site. The simulations also revealed a phenylalanine barrier that controls further access of HDL-derived lipids to the CETP tunnel, providing new atomistic detail on the CETP-HDL interaction mechanism relevant to future therapeutic strategies.
Original abstract
Inhibition of cholesterol ester transfer protein (CETP), a protein mediating transfer of neutral lipids between lipoproteins, has been proposed as a means to elevate atheroprotective HDL subpopulations and thereby reduce atherosclerosis. However, off-target and adverse effects of the inhibition have raised doubts about the molecular mechanism of CETP-HDL interaction. Recent experimental findings have demonstrated the penetration of CETP into HDL. However, atomic level resolution of CETP penetration into HDL, a prerequisite for a better understanding of CETP functionality and HDL atheroprotection, is missing. We constructed an HDL particle that mimics the actual human HDL mass composition and investigated for the first time, by large-scale atomistic molecular dynamics, the interaction of an upright CETP with a human HDL-mimicking model. The results demonstrated how CETP can penetrate the HDL particle surface, with the formation of an opening in the N barrel domain end of CETP, put in evidence the major anchoring role of a tryptophan-rich region of this domain, and unveiled the presence of a phenylalanine barrier controlling further access of HDL-derived lipids to the tunnel of CETP. The findings reveal novel atomistic details of the CETP-HDL interaction mechanism and can provide new insight into therapeutic strategies.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.