Chakraborty Sandipan, Basu Soumalee
Department of Microbiology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata 700 019, India.
Biophys Chem. 2015 Jul;202:1-12. doi: 10.1016/j.bpc.2015.03.006. Epub 2015 Mar 25.
β-secretase 1 (BACE1) initiates the proteolysis of amyloid precursor protein (APP) to generate Aβ, aggregation of which has been considered to be the main histopathological feature of Alzheimer's Disease. Here, we have explored the conformational switching of BACE1 during APP recognition using molecular dynamics simulation thereby suggesting the recognition to be a conformational selection process. Free BACE1 is highly flexible and exists as an ensemble of conformations. The β-hairpin flap that covers the active site of BACE1 visits numerous conformations during the simulation. Essential dynamics reveal that concerted movements in several loops including the flap region lead to a conformational switching from open to closed form. During the simulation, free BACE1 visits both the open and closed forms multiple times. Binding of APP to the BACE1 cavity shifts the equilibrium towards a stable complex stabilized by strong electrostatic surface complementarity along with several van der Waals and hydrogen bonding interactions.
β-分泌酶1（BACE1）启动淀粉样前体蛋白（APP）的蛋白水解以生成Aβ，其聚集被认为是阿尔茨海默病的主要组织病理学特征。在此，我们利用分子动力学模拟探索了BACE1在识别APP过程中的构象转换，从而表明这种识别是一个构象选择过程。游离的BACE1具有高度的灵活性，以多种构象形式存在。覆盖BACE1活性位点的β-发夹瓣在模拟过程中呈现出多种构象。主成分分析表明，包括瓣区在内的几个环中的协同运动导致了从开放形式到封闭形式的构象转换。在模拟过程中，游离的BACE1多次呈现开放和封闭形式。APP与BACE1腔的结合通过强烈的静电表面互补以及多种范德华力和氢键相互作用，使平衡向稳定的复合物移动。
