Can Second Coordination Sphere and Long-Range Interactions Modulate Hydrogen Atom Transfer in a Non-Heme Fe(II)-Dependent Histone Demethylase?
Can Second Coordination Sphere and Long-Range Interactions Modulate Hydrogen Atom Transfer in a Non-Heme Fe(II)-Dependent Histone Demethylase?
复制标题
第二个配位球体和远距离相互作用是否可以调节非血红素Fe（II）依赖性组蛋白脱甲基酶中的氢原子转移？
DOI：
10.1021/jacsau.2c00345
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发表时间：
2022-09-26
期刊：
影响因子：
8
通讯作者：
Christov, Christo Z
中科院分区：
文献类型：
--
作者：
Chaturvedi, Shobhit S;Jaber Sathik Rifayee, Simahudeen Bathir;Waheed, Sodiq O;Wildey, Jon;Warner, Cait;Schofield, Christopher J;Karabencheva-Christova, Tatyana G;Christov, Christo Z
Fe（II）依赖性加氧酶利用氢原子转移（HAT）产生无数产物。了解这些酶如何使用动态过程超出了直接附近的活性位点，以控制HAT的选择性和效率是重要的金属酶工程;然而，通过实验获得这样的知识是具有挑战性的。本研究开发了一个计算框架，用于识别第二配位球（SCS），特别是长程（LR）残基相关的催化，通过动态互相关分析（DCCA）使用人类组蛋白去甲基化酶PHF 8（KDM 7 B）作为模型加氧酶。此外，本研究还探讨了SCS和LR残基对HAT反应的影响机理。为了证明该方法的可行性，我们研究了与X连锁智力残疾相关的PHF 8 F279 S临床突变的影响，该突变已被实验证明可以消除PHF 8催化的去甲基化。在协议中，分子动力学（MD）和量子力学/分子力学（QM/MM）的研究表明，在H31- 14 K9 me 2基板的方向和增加的HAT势垒的变化。我们系统地分析了所确定的SCS和LR残基可能影响HAT的途径，通过探索H3 K9 me 2底物方向的变化，域间相关运动，HAT过渡态稳定，反应能量学，电子转移机制和PHF 8的固有电场的改变。重要的是，SCS和LR变化减少了JmjC结构域的α9−α12向Fe（IV）中心的关键运动，这与H31- 14 K9 me 2底物的更紧密结合有关。SCS和LR残基改变酶的内在电场沿着反应坐标和改变个人的能量贡献的残基对TS稳定。总体结果表明，DCCA确实可以识别非活性位点的催化相关的残基。此类动态相关残基的取代可用作调节非血红素Fe（II）和2 OG依赖性酶中HAT的工具。
Fe(II)-dependent oxygenases employ hydrogen atom transfer (HAT) to produce a myriad of products. Understanding how such enzymes use dynamic processes beyond the immediate vicinity of the active site to control the selectivity and efficiency of HAT is important for metalloenzyme engineering; however, obtaining such knowledge by experiments is challenging. This study develops a computational framework for identifying second coordination sphere (SCS) and especially long-range (LR) residues relevant for catalysis through dynamic cross-correlation analysis (DCCA) using the human histone demethylase PHF8 (KDM7B) as a model oxygenase. Furthermore, the study explores the mechanistic pathways of influence of the SCS and LR residues on the HAT reaction. To demonstrate the plausibility of the approach, we investigated the effect of a PHF8 F279S clinical mutation associated with X-linked intellectual disability, which has been experimentally shown to ablate PHF8-catalyzed demethylation. In agreement, the molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) studies showed a change in the H31–14K9me2 substrate orientation and an increased HAT barrier. We systematically analyzed the pathways by which the identified SCS and LR residues may influence HAT by exploring changes in H3K9me2 substrate orientation, interdomain correlated motions, HAT transition state stabilization, reaction energetics, electron transfer mechanism, and alterations in the intrinsic electric field of PHF8. Importantly, SCS and LR variations decrease key motions of α9−α12 of the JmjC domain toward the Fe(IV)-center that are associated with tighter binding of the H31–14K9me2 substrate. SCS and LR residues alter the intrinsic electric field of the enzyme along the reaction coordinate and change the individual energetic contributions of residues toward TS stabilization. The overall results suggest that DCCA can indeed identify non-active-site residues relevant for catalysis. The substitutions of such dynamically correlated residues might be used as a tool to tune HAT in non-heme Fe(II)- and 2OG-dependent enzymes.