Kumalo H M, Soliman Mahmoud E
a Molecular Modelling & Drug Design Research Group, School of Health Sciences, University of KwaZulu-Natal , Westville , Durban , South Africa.
J Recept Signal Transduct Res. 2016 Oct;36(5):505-14. doi: 10.3109/10799893.2015.1130058. Epub 2016 Jan 24.
Beta-amyloid precursor protein cleavage enzyme1 (BACE1) and beta-amyloid precursor protein cleavage enzyme2 (BACE2), members of aspartyl protease family, are close homologs and have high similarity in their protein crystal structures. However, their enzymatic properties are different, which leads to different clinical outcomes. In this study, we performed sequence analysis and all-atom molecular dynamic (MD) simulations for both enzymes in their ligand-free states in order to compare their dynamical flap behaviors. This is to enhance our understanding of the relationship between sequence, structure and the dynamics of this protein family. Sequence analysis shows that in BACE1 and BACE2, most of the ligand-binding sites are conserved, indicative of their enzymatic property as aspartyl protease members. The other conserved residues are more or less unsystematically localized throughout the structure. Herein, we proposed and applied different combined parameters to define the asymmetric flap motion; the distance, d1, between the flap tip and the flexible region; the dihedral angle, φ, to account for the twisting motion and the TriCα angle, θ2 and θ1. All four combined parameters were found to appropriately define the observed "twisting" motion during the flaps different conformational states. Additional analysis of the parameters indicated that the flaps can exist in an ensemble of conformations, i.e. closed, semi-open and open conformations for both systems. However, the behavior of the flap tips during simulations is different between BACE1 and BACE2. The BACE1 active site cavity is more spacious as compared to that of BACE2. The analysis of 10S loop and 113S loop showed a similar trend to that of flaps, with the BACE1 loops being more flexible and less stable than those of BACE2. We believe that the results, methods and perspectives highlighted in this report would assist researchers in the discovery of BACE inhibitors as potential Alzheimer's disease therapies.
β-淀粉样前体蛋白裂解酶1（BACE1）和β-淀粉样前体蛋白裂解酶2（BACE2）属于天冬氨酸蛋白酶家族成员，是紧密的同源物，其蛋白质晶体结构具有高度相似性。然而，它们的酶学性质不同，导致了不同的临床结果。在本研究中，我们对两种酶的无配体状态进行了序列分析和全原子分子动力学（MD）模拟，以比较它们动态的瓣片行为。这是为了加深我们对该蛋白家族序列、结构和动力学之间关系的理解。序列分析表明，在BACE1和BACE2中，大多数配体结合位点是保守的，这表明它们作为天冬氨酸蛋白酶家族成员的酶学性质。其他保守残基或多或少无系统地分布在整个结构中。在此，我们提出并应用了不同的组合参数来定义不对称瓣片运动；瓣片尖端与柔性区域之间的距离d1；用于解释扭转运动的二面角φ以及三Cα角θ2和θ1。发现所有这四个组合参数都能恰当地定义瓣片在不同构象状态下观察到的“扭转”运动。对这些参数的进一步分析表明，瓣片可以存在于一系列构象中，即两个系统的闭合、半开放和开放构象。然而，在模拟过程中，BACE1和BACE2的瓣片尖端行为有所不同。与BACE2相比，BACE1的活性位点腔更宽敞。对10S环和113S环的分析显示出与瓣片类似的趋势，BACE1的环比BACE2的环更灵活且更不稳定。我们相信，本报告中强调的结果、方法和观点将有助于研究人员发现作为潜在阿尔茨海默病治疗药物的BACE抑制剂。
