Electrostatics and water occlusion regulate covalently-bound flavin mononucleotide cofactors of Vibrio cholerae respiratory complex NQR.
Electrostatics and water occlusion regulate covalently-bound flavin mononucleotide cofactors of Vibrio cholerae respiratory complex NQR.
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DOI：
10.1002/prot.26158
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发表时间：
2021-10
期刊：
影响因子：
2.9
通讯作者：
Minh DDL
中科院分区：
文献类型：
--
作者：
Willow SY;Yuan M;Juárez O;Minh DDL
NADH：泛醌氧化还原酶 (NQR) 等蛋白质是多种病原菌生理学中必需的酶和离子泵，可严格调节其辅助因子的氧化还原特性。尽管黄素单核苷酸 (FMN) 在水溶液中被完全还原，但 NQR 亚基 B 和 C 中的 FMN 在其催化循环期间仅经历单电子跃迁。在这里，我们进行从头计算和分子动力学模拟，以阐明 NQR 中调节 FMN 氧化还原态的机制。 QM/MM 计算表明，结合位点静电不利于 FMNH2 的阴离子形式，但允许完全还原的黄素的中性形式。势能表面不受 FMN 和苏氨酸之间共价键的影响。分子动力学模拟表明，水无法接近 FMN 结合位点，这表明水和其他质子供体的可用性限制或禁止了辅助因子的进一步减少。这些发现让我们更深入地了解 NQR 通过辅助因子调节电子转移并发挥其生理作用的机制。据我们所知，它们还首次提供了蛋白质通过水封闭调节黄素氧化还原状态这一简单概念的证据。
Proteins like NADH:ubiquinone oxidoreductase (NQR), an essential enzyme and ion pump in the physiology of several pathogenic bacteria, tightly regulate the redox properties of their cofactors. Although flavin mononucleotide (FMN) is fully reduced in aqueous solution, FMN in subunits B and C of NQR exclusively undergo one-electron transitions during its catalytic cycle. Here, we perform ab initio calculations and molecular dynamics simulations to elucidate the mechanisms that regulate the redox state of FMN in NQR. QM/MM calculations show that binding site electrostatics disfavor anionic forms of FMNH2, but permit a neutral form of the fully reduced flavin. The potential energy surface is unaffected by covalent bonding between FMN and threonine. Molecular dynamics simulations show that the FMN binding sites are inaccessible by water, suggesting that further reductions of the cofactors are limited or prohibited by the availability of water and other proton donors. These findings provide a deeper understanding of the mechanisms used by NQR to regulate electron transfer through the cofactors and perform its physiologic role. They also provide the first, to our knowledge, evidence of the simple concept that proteins regulate flavin redox states via water occlusion.
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影响因子：
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作者：
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