Emmanuel Iwuchukwu A, Olotu Fisayo A, Agoni Clement, Soliman Mahmoud E S
Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.
Chem Biodivers. 2019 Jun;16(6):e1900085. doi: 10.1002/cbdv.201900085. Epub 2019 May 28.
The discovery of J147 represented a significant milestone in the treatment of age-related disorders, which was further augmented by the recent identification of mitochondrial ATP synthase as the therapeutic target. However, the underlying molecular events associated with the modulatory activity of J147 have remained unresolved till date. Herein, we present, for the first time, a dynamical approach to investigate the allosteric regulation of mATP synthase by J147, using a reliable human αγβ protein model. The highlight of our findings is the existence of the J147-bound protein in distinct structural associations at different MD simulation periods coupled with concurrent open↔close transitions of the β catalytic and α allosteric (ATP5A) sites as defined by Cα distances (d), TriCα (Θ) and dihedral (φ) angular parameters. Firstly, there was an initial pairing of the αγ subunits away from the β subunit followed by the formation of the 'non-catalytic' αβ pair at a distance from the γ subunit. Interestingly, J147-induced structural arrangements were accompanied by the systematic transition of the β catalytic site from a closed to an open state, while there was a concurrent transition of the allosteric site from an open α conformation to a closed state. Consequentially, J147 reduced the structural activity of the whole αγβ complex, while the unbound system exhibited high atomistic deviations and structural flexibility. Furthermore, J147 exhibited favorable binding at the allosteric site of mATP synthase with considerable electrostatic energy contributions from Gln215, Gly217, Thr219, Asp312, Asp313, Glu371 and Arg406. These findings provide details on the possible effects of J147 on mitochondrial bioenergetics, which could facilitate the structure-based design of novel small-molecule modulators of mATP synthase in the management of Alzheimer's disease and other neurodegenerative disorders.
J147的发现代表了与年龄相关疾病治疗中的一个重要里程碑，最近将线粒体ATP合酶确定为治疗靶点进一步增强了这一里程碑意义。然而，迄今为止，与J147调节活性相关的潜在分子事件仍未得到解决。在此，我们首次提出一种动力学方法，使用可靠的人类αγβ蛋白模型来研究J147对线粒体ATP合酶的变构调节。我们研究结果的亮点是，在不同的分子动力学模拟阶段，J147结合蛋白存在于不同的结构关联中，同时β催化位点和α变构（ATP5A）位点由Cα距离（d）、TriCα（Θ）和二面角（φ）角参数定义的同时发生开放↔关闭转变。首先，αγ亚基最初与β亚基分离配对，随后在与γ亚基有一定距离处形成“非催化性”αβ对。有趣的是，J147诱导的结构排列伴随着β催化位点从关闭状态到开放状态的系统转变，而变构位点同时从开放的α构象转变为关闭状态。因此，J147降低了整个αγβ复合物的结构活性，而未结合的系统表现出高原子偏差和结构灵活性。此外，J147在mATP合酶的变构位点表现出良好的结合，Gln215、Gly217、Thr219、Asp312、Asp313、Glu371和Arg406提供了相当大的静电能贡献。这些发现提供了J147对线粒体生物能量学可能影响的详细信息，这可能有助于基于结构设计新型mATP合酶小分子调节剂，用于治疗阿尔茨海默病和其他神经退行性疾病。
