Niemelä Akseli, Koivuniemi Artturi
Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
PLoS Comput Biol. 2021 Mar 15;17(3):e1008426. doi: 10.1371/journal.pcbi.1008426. eCollection 2021 Mar.
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.
卵磷脂胆固醇酰基转移酶蛋白（LCAT）促进胆固醇与磷脂衍生的酰基链之间的酯化反应。已经开发出正变构调节剂来治疗LCAT缺乏症，并且有望在未来也用于治疗心血管疾病。这些化合物的作用机制尚不清楚。在这里，利用计算对接和原子分子动力学模拟来研究LCAT与激活化合物之间的相互作用。结果表明，所有药物都以类似的方式结合到膜结合结构域的变构结合口袋中。变构位点中化合物的存在导致膜结合结构域（MBD）的独特空间取向和取样。正如引导分子动力学模拟所表明的，MBD不同的空间排列可能会影响盖子从关闭状态到打开状态的移动，反之亦然。
