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.
Highlights
Supplementary key words atherosclerosis cholesterol/trafficking estrogen high density lipoprotein/metabolism lipid transfer protein lipoproteins cholesterol ester transfer protein molecular dynamics the atheroprotective functions of HDL [1] have been driving forces for research on HDL as a potential therapeutic target [2]
Despite seeming agreement of these general changes experienced by the double superhelix (DSH) model with [13], highlighting of the phosphate of the POPC head groups (Fig. 2C) offers a clear view of the significant reorganization experienced by the DSH nascent HDL model over our molecular dynamics (MD) simulation
The present results demonstrate that our force field can generate relevant structural data, which is a prerequisite for further MD studies
Summary
The HDL model was a lipid-mimicking droplet of HDL containing phospholipids (POPC) and cholesteryl ester, lacking the HDL main protein, apoA-I. By modeling a HDL particle of actual human HDL mass composition in association with E2 fatty acyl ester, we can further both studies, with the aim of clarifying lipid exchange, such as cholesteryl ester [cholesteryl oleate (ChOE)] transfer from HDL to CETP, and possible E2 fatty acyl ester transfer from HDL to CETP. We present details of the modeling of HDL, proceeding from a starting nascent model of HDL [11,12,13] to the construction of spherical HDL models mimicking actual human HDL mass composition, and explore the interaction of these with CETP.
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