Vivek Sharma
Petra Imhof
Petra Hellwig- 1University of Helsinki, Helsinki, Finland
- 2Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
- 3Université de Strasbourg, Strasbourg, France
Editorial on the Research Topic
Computational and Experimental Insights in Redox-Coupled Proton Pumping in Proteins
Elementary electron and proton transfer reactions commonly occur in chemistry and biology. Proteins involved in oxidative- and photo-phosphorylation carry out these reactions to generate energy in the form of ATP. Despite the simplicity of electron and proton transfer reactions, these pose extreme challenge to study either by experimental or computational approaches. In this special issue, we present a collection of reviews, original research articles as well as perspectives written by top-level experimental and computational experts working in the field of redox-active enzymes and associated fields. The special issue presents a current state-of-the-art in our understanding of the mechanism of bioenergetic enzymes, and at the same time provides important glimpses of theoretical and experimental methodological advances in the field.
The respiratory complex I, NADH:quinone (Q) oxidoreductase, is the first electron acceptor of the electron transport chain (ETC) in many organisms and pumps protons by conserving energy from the reduction of quinone to quinol (Parey et al., 2020). Despite recent major advances in structural characterization of this large complex (500–1 MDa), the molecular mechanism of redox-coupled proton pumping remains largely unknown and among other questions, the role of quinone/quinol binding in the electrostatic and conformational control of enzyme remains unclear (Hielscher et al., 2013; Haapanen and Sharma, 2021). One of the central elements of the coupling mechanism is the interface between the peripheral “arm” catalysing electron transfer and a membrane “arm” responsible for proton translocation. In this special issue, Yoga et al. and Nuber et al. have reviewed and discussed interesting aspects of quinone/quinol binding and its coupling to the conformational changes in this critical region of complex I. Yoga et al. reviewed the latest structural and computational data on the binding of quinone in the unique ∼30 Å long quinone-binding tunnel of complex I, and discussed recent mechanistic models of proton pumping. Nuber et al. have highlighted the importance of movement of quinol (QH−) anion in the quinone tunnel and protonation/deprotonation reactions in the redox-coupled proton pumping mechanism of complex I.
The third complex in the ETC is complex III and is described by a well-known Q cycle (Crofts et al., 2017). Husen and Solov’yov gave new insights into the side-reactions of complex III, and by performing multiscale computational simulations they suggest how superoxide forms by reaction between dioxygen and semiquinone, and how it is released to the membrane-solvent environment. Thus, shedding light on the ROS (reactive oxygen species) generation by complex III of the ETC. Sarewicz et al. by performing site-directed mutagenesis of heme bL ligand and spectroscopic measurements provided new insights into the redox reactions of Qo site of complex III.
The final electron acceptor, complex IV, acts as an electron sink in the ETC of many organisms, and efficiently pumps protons by conserving the free energy of oxygen reduction (Wikström and Sharma, 2018). The functional importance of a tyrosyl radical in the catalytic cycle of complex IV has been emphasized based on computations and experiments (Voicescu et al., 2009; Sharma et al., 2013). Blomberg, based on hybrid density functional theory calculations (Blomberg) discusses how highly conserved redox-active tyrosine remains deprotonated until the last steps of the catalytic cycle, a notion that is central to drive proton pumping even at high proton motive force. Baserga et al. performed advanced FTIR spectroelectrochemical titrations and provided a quantitative description of the changes in electric field at the active site of complex IV during its redox reactions.
Kaur and colleagues provide a holistic view on the proton binding motifs of the redox-active proton pumps. They highlight the central role played by proton loading sites (sites in protein that uptake and release protons) in maintaining pumping even at high proton motive force. Relatedly, Bondar presents a comparison of several proton translocating enzymes and their proton binding motifs, and emphasizes the importance of these in understanding mechanism of proton pumping enzymes. In the study of Calisto and Pereira, sequence and structural analysis of NrfD-like subunits is presented and their role in ion-translocation and quinone binding is discussed.
Other complex electron and proton translocating enzymes are presented, completing the picture on the complexity of coupled electron and proton translocation in biological systems. Wu et al. reveal the complex electron transfer in NADPH oxidase 5 (NOX5), a member of a family of enzymes, dedicated to the production of reactive oxygen species. By computer simulations, they analysed the O2 movement and electron tunneling pathways in the inter-heme electron-transfer steps that ultimately lead to production of superoxide in NOX5. Finally, Dale-Evans et al. describe the mechanism of HypD from E. coli by means of theoretical and computational studies on the voltametric current. Their data allowed them to specifically estimate the kinetic parameter and reveal a step-wise one-electron, one-proton transfer mechanism rather than a concerted two-electron redox reaction.
The work presented in this special issue highlights how experimental (spectroscopy, biochemistry, etc.) and computational (classical and quantum chemical simulations) studies in concert have greatly advanced our knowledge of proton-coupled electron transfer processes. Even with the broad range of exciting results and mechanistic understanding already obtained, the complexity of the systems involved in redox-coupled proton pumping is so high that novel developments at all levels will be needed in years and decades to come.
Author Contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
Crofts, A. R., Rose, S. W., Burton, R. L., Desai, A. V., Kenis, P. J. A., and Dikanov, S. A. (2017). The Q-Cycle Mechanism of the bc1 Complex: A Biologist’s Perspective on Atomistic Studies. J. Phys. Chem. B 121, 3701–3717. doi:10.1021/acs.jpcb.6b10524
Haapanen, O., and Sharma, V. (2021). Redox- and Protonation-State Driven Substrate-Protein Dynamics in Respiratory Complex I. Curr. Opin. Electrochem. 29, 100741. doi:10.1016/j.coelec.2021.100741
Hielscher, R., Yegres, M., Voicescu, M., Gnandt, E., Friedrich, T., and Hellwig, P. (2013). Characterization of Two Quinone Radicals in the NADH:Ubiquinone Oxidoreductase from Escherichia coli by a Combined Fluorescence Spectroscopic and Electrochemical Approach. Biochemistry 52, 8993–9000. doi:10.1021/bi4009903
Parey, K., Wirth, C., Vonck, J., and Zickermann, V. (2020). Respiratory Complex I — Structure, Mechanism and Evolutionls. Curr. Opin. Struct. Biol. 63, 1–9. doi:10.1016/j.sbi.2020.01.004
Sharma, V., Karlin, K. D., and Wikström, M. (2013). Computational Study of the Activated OH State in the Catalytic Mechanism of Cytochrome c Oxidase. Proc. Nat. Acad. Sci. USA 110, 16844–16849. doi:10.1073/pnas.1220379110
Voicescu, M., El Khoury, Y., Martel, D., Heinrich, M., and Hellwig, P. (2009). Spectroscopic Analysis of Tyrosine Derivatives: On the Role of the Tyrosine–Histidine Covalent Linkage in Cytochrome c Oxidase. J. Phys. Chem. B 113, 13429. doi:10.1021/jp9048742
Keywords: cell respiration, photosynthesis, proton-coupled electron donor, molecular dynamics simulation, quantum chemical calculation, spectroscopy, mitochondria, reactive oxygen species (ROS)
Citation: Sharma V, Imhof P and Hellwig P (2021) Editorial: Computational and Experimental Insights in Redox-Coupled Proton Pumping in Proteins. Front. Chem. 9:762612. doi: 10.3389/fchem.2021.762612
Received: 22 August 2021; Accepted: 03 September 2021;
Published: 15 September 2021.
Edited by and Reviewed:
Antonio Monari, UMR7019 Laboratoire de Physique et Chimie Théoriques, FranceCopyright © 2021 Sharma, Imhof and Hellwig. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Vivek Sharma, vivek.sharma@helsinki.fi