Cyclic Changes in Active Site Polarization and Dynamics Drive the 'Ping-pong' Kinetics in NRH:Quinone Oxidoreductase 2: An Insight from QM/MM Simulations.
Cyclic Changes in Active Site Polarization and Dynamics Drive the 'Ping-pong' Kinetics in NRH:Quinone Oxidoreductase 2: An Insight from QM/MM Simulations.
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DOI：
10.1021/acscatal.8b04193
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发表时间：
2018-11
期刊：
影响因子：
12.9
通讯作者：
Clorice R. Reinhardt;Quin H. Hu;Caitlin G. Bresnahan;S. Hati;S. Bhattacharyya
中科院分区：
文献类型：
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作者：
Clorice R. Reinhardt;Quin H. Hu;Caitlin G. Bresnahan;S. Hati;S. Bhattacharyya
醌还原酶属于黄素依赖性氧化还原酶家族。与氧化还原活性辅因子，黄素腺嘌呤二核苷酸，醌还原酶是已知的利用“乒乓”的动力学机制，在催化过程中，氢化物之间的黄素和它的两个底物来回反弹。然而，该催化循环的继续需要产物置换步骤，其中一个氧化还原半循环的产物被下一个半循环的底物置换。采用改进的混合量子力学/分子力学模拟方法，研究了NRH：醌氧化还原酶2中的催化氢化物转移和产物置换反应。首先，自洽的电荷密度泛函紧束缚理论被用来描述黄素环和底物原子，而嵌入在分子机械处理的溶剂化活性位点。然后，对于催化循环的每一步，使用基于密度泛函理论的修正进行了能量学的进一步改进。本研究展示了一个综合的相互作用的溶剂化，质子化和蛋白质基质诱导的极化作为背后的驱动力的热力学车轮的“乒乓”动力学。这里报道的是第一原理模型的“乒乓”动力学，描绘了如何在活性位点的极化和动力学的周期性变化，治理振荡的氢化物转移和产品的位移在这种酶。
Quinone reductases belong to the family of flavin-dependent oxidoreductases. With the redox active cofactor, flavin adenine dinucleotide, quinone reductases are known to utilize a 'ping-pong' kinetic mechanism during catalysis in which a hydride is bounced back and forth between flavin and its two substrates. However, the continuation of this catalytic cycle requires product displacement steps, where the product of one redox half-cycle is displaced by the substrate of the next half-cycle. Using improved hybrid quantum mechanical/molecular mechanical simulations, both the catalytic hydride transfer and the product displacement reactions were studied in NRH:quinone oxidoreductase 2. Initially, the self-consistent charge-density functional tight binding theory was used to describe flavin ring and the substrate atoms, while embedded in the molecular mechanically-treated solvated active site. Then, for each step of the catalytic cycle, a further improvement of energetics was made using density functional theory-based corrections. The present study showcases an integrated interplay of solvation, protonation, and protein matrix-induced polarization as the driving force behind the thermodynamic wheel of the 'ping-pong' kinetics. Reported here is the first-principles model of the 'ping-pong' kinetics that portrays how cyclic changes in the active site polarization and dynamics govern the oscillatory hydride transfer and product displacement in this enzyme.