John_2014_Mol.Divers_18_119

Primary hypercholesterolemia is the root cause for major health issues like coronary heart disease and atherosclerosis. Regulating plasma cholesterol level, which is the product of biosynthesis as well as dietary intake, has become one of the major therapeutic strategies to effectively control these diseases. Human cholesterol esterase (hCEase) is an interesting target involved in the regulation of plasma cholesterol level and thus inhibition of this enzyme is highly effective in the treatment of hypercholesterolemia. This study was designed to understand the activation mechanism that enables the enzyme to accommodate long chain fatty acids and to identify the structural elements for the successful catalysis. Primarily the activation efficiencies of three different bile salts were studied and compared using molecular dynamics simulations. Based on the conformations of major surface loops, hydrogen bond interactions, and distance analyses, taurocholate was concluded as the preferred activator of the enzyme. Furthermore, the importance of two bile salt binding sites (proximal and remote) and the crucial role of 7alpha-OH group of the bile salts in the activation of hCEase was examined and evidenced. The results of our study explain the structural insights of the activation mechanism and show the key features of the bile salts responsible for the enzyme activation which are very useful in hypolipidemic drug designing strategies.