Modeling the Energy Landscape of Side Reactions in the Cytochrome bc1 Complex

Peter Husen, Ilia A. Solov’yov*

*Corresponding author for this work

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Much of the metabolic molecular machinery responsible for energy transduction processes in living organisms revolves around a series of electron and proton transfer processes. The highly redox active enzymes can, however, also pose a risk of unwanted side reactions leading to reactive oxygen species, which are harmful to cells and are a factor in aging and age-related diseases. Using extensive quantum and classical computational modeling, we here show evidence of a particular superoxide production mechanism through stray reactions between molecular oxygen and a semiquinone reaction intermediate bound in the mitochondrial complex III of the electron transport chain, also known as the cytochrome b c 1 complex. Free energy calculations indicate a favorable electron transfer from semiquinone occurring at low rates under normal circumstances. Furthermore, simulations of the product state reveal that superoxide formed at the Q o -site exclusively leaves the b c 1 complex at the positive side of the membrane and escapes into the intermembrane space of mitochondria, providing a critical clue in further studies of the harmful effects of mitochondrial superoxide production.

Original languageEnglish
Article number643796
JournalFrontiers in Chemistry
Number of pages14
Publication statusPublished - May 2021

Bibliographical note

Publisher Copyright:
© Copyright © 2021 Husen and Solov’yov.


  • computational biophysics
  • electron transfer
  • enzymes
  • free energy perturbation
  • molecular dynamics
  • proteins
  • quantum chemical modeling
  • superoxide


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