Abstract
Lecithin:cholesterol acyltransferase protein (LCAT) promotes the esterification reaction between cholesterol and phospholipid-derived acyl chains. Positive allosteric modulators have been developed to treat LCAT deficiencies and, plausibly, also cardiovascular diseases in the future. The mechanism of action of these compounds is poorly understood. Here computational docking and atomistic molecular dynamics simulations were utilized to study the interactions between LCAT and the activating compounds. Results indicate that all drugs bind to the allosteric binding pocket in the membrane-binding domain in a similar fashion. The presence of the compounds in the allosteric site results in a distinct spatial orientation and sampling of the membrane-binding domain (MBD). The MBD’s different spatial arrangement plausibly affects the lid’s movement from closed to open state and vice versa, as suggested by steered molecular dynamics simulations.
Highlights
Lecithin:cholesterol acyltransferase (LCAT) is an enzyme that is responsible for producing cholesterol esters (CEs) in circulation by linking the acyl chains of phospholipids to cholesterol (CHOL) molecules
In order to investigate the differences between the binding poses of different compounds and to produce starting configurations for atomistic molecular dynamics simulations, all compounds were docked to the membrane-binding domain (MBD) of LCAT (PDB accession code: 6MVD, co-crystallized with compound 1b) utilizing the AutoDock Vina docking software [26]
We aimed to characterize how a set of positive allosteric modulators interact with LCAT, firstly, to produce new insights on how these modulators mechanistically promote the activity and, secondly, shed light on the general activation mechanism of LCAT mediated by different apolipoproteins, apolipoprotein A-I (apoA-I)
Summary
Lecithin:cholesterol acyltransferase (LCAT) is an enzyme that is responsible for producing cholesterol esters (CEs) in circulation by linking the acyl chains of phospholipids to cholesterol (CHOL) molecules. LCAT mediated CE formation predominantly occurs in high-density lipoprotein (HDL) particles in which apolipoprotein A-I (apoA-I) serves as a cofactor for the reaction. After the formation of CEs, the morphology of HDL particles transforms from discoidal to spherical by the creation of a non-polar CE phase, which is shielded from aqueous surroundings by an amphiphilic monolayer comprised of phospholipids, CHOL, and apolipoproteins. HDL particles remove CHOL from lipid droplet-laden macrophages that are the hallmark of early atherosclerotic lesions in the arterial intima [1]. For this reason, RCT’s efficiency is hypothesized to be associated with the progression of coronary heart disease (CHD) [2,3,4]
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