부산대학교 도서관

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. Author summary: High-density lipoprotein (HDL) particles play a crucial role in reverse cholesterol transport, whose efficiency is linked to the development of coronary heart disease (CHD), a global health threat showing an increased prevalence in industrial as well as in developing countries. While many drugs for treating CHD exist, e.g., the cholesterol-lowering statins, a substantial residual vascular risk remains, thus calling for novel therapeutic interventions. One of these approaches is to elevate the activity of lecithin:cholesterol acyltransferase (LCAT) enzyme by, e.g., positive allosteric modulators. However, although modulators' allosteric binding site is known, it is not understood how these compounds can promote the activity LCAT. Therefore, in this article, we aimed to clarify how a set of positive allosteric modulators affect the structural and dynamical properties of LCAT utilizing atomistic molecular dynamics simulations and free energy calculations. Shortly, our findings suggest that the reorientation and the different energetic landscape of the MBD induced by the allosteric compounds may facilitate the lid's opening, therefore providing a plausible explanation of why the set of positive allosteric modulators promote the activity of LCAT. Besides, this finding is also insightful when deciphering how apoA-I, the principal LCAT activating apolipoprotein in HDL particles, facilitates the activation of LCAT. [ABSTRACT FROM AUTHOR]