Mechanistic Insights on Heme-to-Heme Transmembrane Electron Transfer Within NADPH Oxydases From Atomistic Simulations.

Autor: Wu X; CNRS, Université de Paris, UPR 9080, Laboratoire de Biochimie Théorique, Paris, France.; Institut de Biologie Physico-Chimique-Fondation Edmond de Rotschild, PSL Research University, Paris, France., Hénin J; CNRS, Université de Paris, UPR 9080, Laboratoire de Biochimie Théorique, Paris, France.; Institut de Biologie Physico-Chimique-Fondation Edmond de Rotschild, PSL Research University, Paris, France., Baciou L; Institut de Chimie Physique, Université Paris Saclay, CNRS (UMR 8000), Orsay, France., Baaden M; CNRS, Université de Paris, UPR 9080, Laboratoire de Biochimie Théorique, Paris, France.; Institut de Biologie Physico-Chimique-Fondation Edmond de Rotschild, PSL Research University, Paris, France., Cailliez F; Institut de Chimie Physique, Université Paris Saclay, CNRS (UMR 8000), Orsay, France., de la Lande A; Institut de Chimie Physique, Université Paris Saclay, CNRS (UMR 8000), Orsay, France.
Jazyk: angličtina
Zdroj: Frontiers in chemistry [Front Chem] 2021 May 04; Vol. 9, pp. 650651. Date of Electronic Publication: 2021 May 04 (Print Publication: 2021).
DOI: 10.3389/fchem.2021.650651
Abstrakt: NOX5 is a member of the NADPH oxidase family which is dedicated to the production of reactive oxygen species. The molecular mechanisms governing transmembrane electron transfer (ET) that permits to shuttle electrons over the biological membrane have remained elusive for a long time. Using computer simulations, we report conformational dynamics of NOX5 embedded within a realistic membrane environment. We assess the stability of the protein within the membrane and monitor the existence of cavities that could accommodate dioxygen molecules. We investigate the heme-to-heme electron transfer. We find a reaction free energy of a few tenths of eV (ca. -0.3 eV) and a reorganization free energy of around 1.1 eV (0.8 eV after including electrostatic induction corrections). The former indicates thermodynamically favorable ET, while the latter falls in the expected values for transmembrane inter-heme ET. We estimate the electronic coupling to fall in the range of the μeV. We identify electron tunneling pathways showing that not only the W378 residue is playing a central role, but also F348. Finally, we reveal the existence of two connected O 2- binding pockets near the outer heme with fast exchange between the two sites on the nanosecond timescale. We show that when the terminal heme is reduced, O 2 binds closer to it, affording a more efficient tunneling pathway than when the terminal heme is oxidized, thereby providing an efficient mechanism to catalyze superoxide production in the final step. Overall, our study reveals some key molecular mechanisms permitting reactive oxygen species production by NOX5 and paves the road for further investigation of ET processes in the wide family of NADPH oxidases by computer simulations.
Competing Interests: 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.
(Copyright © 2021 Wu, Hénin, Baciou, Baaden, Cailliez and de la Lande.)
Databáze: MEDLINE
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