Interplay of flavin's redox states and protein dynamics: an insight from QM/MM simulations of dihydronicotinamide riboside quinone oxidoreductase 2.
Interplay of flavin's redox states and protein dynamics: an insight from QM/MM simulations of dihydronicotinamide riboside quinone oxidoreductase 2.
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黄素氧化还原态与蛋白质动力学的相互作用：二氢烟酰胺核苷醌氧化还原酶 2 的 QM/MM 模拟的见解。
DOI：
10.1021/jp1107922
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Bhattacharyya,Sudeep
中科院分区：
文献类型：
--
作者：
Mueller,RobynM;North,MichaelA;Yang,Chee;Hati,Sanchita;Bhattacharyya,Sudeep
已知二氢烟酰胺核苷醌氧化还原酶2利用其辅因子黄素腺嘌呤二核苷酸催化对苯二酚的两电子还原反应。利用量子力学/分子力学模拟方法，计算了黄素在自由态和结合在酶活性中心时的电子和质子转移过程的重组自由能。计算的电子转移过程的能量学表明，与无酶的水相相比，酶活性中心降低了氧化还原过程的重组能。这一点在两个电子还原步骤中最为明显，该步骤消除了黄半喹酮生成的可能性。此外，对模拟运动的基本动力学研究表明，随着黄素的还原，原子涨落的主成分发生了惊人的变化。活性部位动力学的这种变化提供了一个洞察酶在酶结合的黄素氧化还原状态改变时所表现出的“乒乓球”动力学。电荷微扰分析进一步支持了观察到的动力学变化与由于黄素环和活性中心残基之间的静电相互作用改变而导致的能级变化相关。这项研究表明，静电预组织的影响超过了化学催化，因为它强烈地影响了催化后的内在蛋白质动力学。
Dihydronicotinamide riboside quinone oxidoreductase 2 is known to catalyze a two-electron reduction of quinone to hydroquinone using its cofactor, flavin adenine dinucleotide. Using quantum mechanical/molecular mechanical simulations, we have computed the reorganization free energies of the electron and proton transfer processes of flavin in the free state as well as when it is bound in the active site of the enzyme. The calculated energetics for electron transfer processes demonstrate that the enzyme active site lowers the reorganization energy for the redox process as compared to the enzyme-free aqueous state. This is most apparent in the two electron reduction step, which eliminates the possibility of flavosemiquinone generation. In addition, essential dynamics study of the simulated motions revealed spectacular changes in the principal components of atomic fluctuations upon reduction of flavin. This alteration of active site dynamics provides an insight into the “ping-pong” kinetics exhibited by the enzyme upon a change in the redox state of the enzyme-bound flavin. A charge perturbation analysis provides further support that the observed change in dynamics is correlated with the change in energetics due to the altered electrostatic interactions between the flavin ring and the active site residues. This study shows that the effect of electrostatic preorganization goes beyond the chemical catalysis as it strongly impacts the postcatalytic intrinsic protein dynamics.