Singh Niven, Zhang Peng, Beratan David N
Department of Biostatistics and Bioinformatics, Duke University Durham NC 27710 USA.
Department of Chemistry, Duke University Durham NC 27708 USA.
Chem Sci. 2025 Aug 27. doi: 10.1039/d5sc02960k.
Biology uses relatively few electron-transfer cofactors, tuning their potentials, electronic couplings, and reorganization energies to carry out the required chemistry. It is remarkable that the potential ordering of two-electron transfer active flavins can be normal (first oxidation at low potential and second oxidation at high potential) or inverted, and the gap between the potentials can be as large as one volt. Analysis based on structural bioinformatics and electrostatics indicates that the ordering of the flavin redox potential is influenced by protein electrostatics. In all 36 flavoproteins examined, the introduction of a negative charge near the flavin increases the extent of potential inversion (by lowering the electrochemical potential of the second electron-transfer step); the introduction of a positive charge near the flavin favors normally ordered potentials. We also find that the addition of positive charges increases the electrochemical potential for the naturally occurring one-electron transition in flavodoxins (between deprotonated hydroquinone and neutral semiquinone) and also increases the second one-electron transition in bifurcating flavins (between anionic semiquinone and fully oxidized flavin). Finally, we find that proximity of a proton acceptor, notably conserved arginine, supports proton-coupled electron transfer because it may act as a proton acceptor, promoting potential inversion. This key arginine residue may enable two-electron transfer chemistry by promoting the proton-coupled electron transfer process over the pure electron transfer process, suggesting how a protein's flavin environment may influence one- or two-electron chemistry in flavoproteins.
生物学中使用的电子转移辅助因子相对较少，通过调节它们的电位、电子耦合和重组能来进行所需的化学反应。值得注意的是，双电子转移活性黄素的电位排序可以是正常的（低电位下首次氧化，高电位下第二次氧化）或反转的，并且电位之间的差距可以高达一伏特。基于结构生物信息学和静电学的分析表明，黄素氧化还原电位的排序受蛋白质静电作用影响。在所研究的所有36种黄素蛋白中，在黄素附近引入负电荷会增加电位反转的程度（通过降低第二个电子转移步骤的电化学电位）；在黄素附近引入正电荷有利于电位正常排序。我们还发现，添加正电荷会增加黄素氧还蛋白中天然存在的单电子跃迁（去质子化对苯二酚和中性半醌之间）的电化学电位，也会增加分叉黄素中第二个单电子跃迁（阴离子半醌和完全氧化的黄素之间）的电化学电位。最后，我们发现质子受体（特别是保守的精氨酸）的接近支持质子耦合电子转移，因为它可能作为质子受体，促进电位反转。这个关键的精氨酸残基可能通过促进质子耦合电子转移过程而非纯电子转移过程来实现双电子转移化学反应，这表明蛋白质的黄素环境可能如何影响黄素蛋白中的单电子或双电子化学反应。
