Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-Universität Düsseldorf, 40225, Düsseldorf, Germany.
John von Neumann Institute for Computing (NIC), Jülich Supercomputing Centre (JSC) & Institute for Complex Systems - Structural Biochemistry (ICS 6), Forschungszentrum Jülich, 52425, Jülich, Germany.
Sci Rep. 2017 Aug 14;7(1):8020. doi: 10.1038/s41598-017-08521-w.
The pyruvate phosphate dikinase (PPDK) reaction mechanism is characterized by a distinct spatial separation of reaction centers and large conformational changes involving an opening-closing motion of the nucleotide-binding domain (NBD) and a swiveling motion of the central domain (CD). However, why PPDK is active only in a dimeric form and to what extent an alternate binding change mechanism could underlie this fact has remained elusive. We performed unbiased molecular dynamics simulations, configurational free energy computations, and rigidity analysis to address this question. Our results support the hypothesis that PPDK dimerization influences the opening-closing motion of the NBDs, and that this influence is mediated via the CDs of both chains. Such an influence would be a prerequisite for an alternate binding change mechanism to occur. To the best of our knowledge, this is the first time that a possible explanation has been suggested as to why only dimeric PPDK is active.
丙酮酸磷酸二激酶（PPDK）的反应机制的特点是反应中心的明显空间分离和涉及核苷酸结合域（NBD）的开闭运动以及中心域（CD）的旋转运动的大构象变化。然而，为什么 PPDK 仅以二聚体形式活跃，以及这种事实在何种程度上可以由替代结合变化机制来解释，仍然难以捉摸。我们进行了无偏分子动力学模拟、构象自由能计算和刚性分析来解决这个问题。我们的结果支持这样一种假设，即 PPDK 二聚化影响 NBDs 的开闭运动，而这种影响是通过两条链的 CDs 介导的。这种影响将是替代结合变化机制发生的前提。据我们所知，这是首次提出了一个可能的解释，即为什么只有二聚体 PPDK 是活跃的。
