Investigation of flap flexibility of β-secretase using molecular dynamic simulations
Investigation of flap flexibility of β-secretase using molecular dynamic simulations
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DOI：
10.1080/07391102.2015.1064831
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发表时间：
2016-01-01
影响因子：
4.4
通讯作者：
Soliman, Mahmoud E.
中科院分区：
文献类型：
--
作者：
Kumalo, Hezekiel M.;Bhakat, Soumendranath;Soliman, Mahmoud E.
瓣基序及其动力学在天冬氨酸蛋白酶中被广泛报道，例如HIV 蛋白酶和血浆蛋白酶。在此，我们首次报道了使用分子动力学模拟对分泌酶不同构象之间的瓣动力学的描述。提出了各种参数，并选择了一些可以适当描述襟翼运动的参数。研究了三个系统，即自由（BACE（Free））和两个配体结合构象，分别属于空间群P6（1）22（BACE（Bound1））和C222（1）（BACE（Bound2））和四个参数（瓣尖残基之间的距离，Thr72和Ser325，d（1）；二面角，phi (苏氨酸72-天冬氨酸32-天冬氨酸228-丝氨酸325)； TriC角，（1）（Thr72-Asp32-Ser325）和（2）（Thr72-Asp228-Ser325））被提出来了解皮瓣域动力学的变化以及皮瓣打开和关闭的程度。对(2)、d(1)、(1)和phi的分析证实BACE(Free)采用半开放、开放和闭合构象，在皮瓣打开时有轻微扭曲。然而，由于配体和瓣尖残基之间缺乏氢键相互作用，BACE(Bound1) (P6122) 显示出对开放构象的适应。在皮瓣打开期间，观察到 BACE(Bound1) 存在轻微的皮瓣扭曲 phi（横向扭曲），这与 BACE(Free) 的打开相关。与 BACE(Bound1) 相反，由于瓣尖残基和配体之间形成稳定的氢键相互作用，BACE(Bound2) 在整个模拟过程中将瓣锁定在闭合构象中。对所有三个系统的分析强调，d(1)、(2) 和 phi 可以精确地用于描述瓣膜打开和关闭的程度，同时沿着跨 β-分泌酶几种构象的分子动力学轨迹进行快照。
Flap motif and its dynamics were extensively reported in aspartate proteases, e.g. HIV proteases and plasmepsins. Herein, we report the first account of flap dynamics amongst different conformations of -secretase using molecular dynamics simulation. Various parameters were proposed and a selected few were picked which could appropriately describe the flap motion. Three systems were studied, namely Free (BACE(Free)) and two ligand-bound conformations, which belonged to space groups P6(1)22 (BACE(Bound1)) and C222(1) (BACE(Bound2)), respectively and four parameters (distance between the flaps tip residue, Thr72 and Ser325, d(1); dihedral angle, phi (Thr72-Asp32-Asp228-Ser325); TriC angles, (1) (Thr72-Asp32-Ser325), and (2) (Thr72-Asp228-Ser325)) were proposed to understand the change in dynamics of flap domain and the extent of flap opening and closing. Analysis of, (2), d(1), (1) and phi confirmed that the BACE(Free) adopted semi-open, open and closed conformations with slight twisting during flap opening. However, BACE(Bound1) (P6122) showed an adaptation to open conformation due to lack of hydrogen bond interaction between the ligand and flap tip residue. A slight flap twisting, phi (lateral twisting) was observed for BACE(Bound1) during flap opening which correlates with the opening of BACE(Free). Contradictory to the BACE(Bound1), the BACE(Bound2) locked the flap in a closed conformation throughout the simulation due to formation of a stable hydrogen bond interaction between the flap tip residue and ligand. Analyses of all three systems highlight that d(1), (2) and phi can be precisely used to describe the extent of flap opening and closing concurrently with snapshots along the molecular dynamics trajectory across several conformations of beta-secretase.