期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：33
DOI：10.1073/pnas.2026169118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
To perform their specific electron-transfer relay functions, hemes commonly adopt low spin states with fine-tuned redox potentials. Understanding molecular elements controlling these properties is crucial for the description of natural proteins and engineering redox-active systems. We describe unusual effects of mitochondrial disease-related mutation in cytochrome
bc
1, based on which we identify a dual role of hydrogen bonding to the propionate group of heme
b
H. We observe that stabilization of the hydrogen bond in mutant enhances the redox potential but destabilizes the low spin state of oxidized heme. This demonstrates a critical role of the hydrogen bonding, and heme-protein interactions in general, to secure a suitable redox potential and spin state, a notion that might be universal for other heme proteins.
Hemes are common elements of biological redox cofactor chains involved in rapid electron transfer. While the redox properties of hemes and the stability of the spin state are recognized as key determinants of their function, understanding the molecular basis of control of these properties is challenging. Here, benefiting from the effects of one mitochondrial disease–related point mutation in cytochrome
b, we identify a dual role of hydrogen bonding (H-bond) to the propionate group of heme
b
H of cytochrome
bc
1, a common component of energy-conserving systems. We found that replacing conserved glycine with serine in the vicinity of heme
b
H caused stabilization of this bond, which not only increased the redox potential of the heme but also induced structural and energetic changes in interactions between Fe ion and axial histidine ligands. The latter led to a reversible spin conversion of the oxidized Fe from 1/2 to 5/2, an effect that potentially reduces the electron transfer rate between the heme and its redox partners. We thus propose that H-bond to the propionate group and heme-protein packing contribute to the fine-tuning of the redox potential of heme and maintaining its proper spin state. A subtle balance is needed between these two contributions: While increasing the H-bond stability raises the heme potential, the extent of increase must be limited to maintain the low spin and diamagnetic form of heme. This principle might apply to other native heme proteins and can be exploited in engineering of artificial heme-containing protein maquettes.
关键词：enmitochondrial dysfunction;electron paramagnetic resonance;electron transfer;molecular dynamics simulations;density functional theory
