AUTHOR=Husen Peter , Solov’yov Ilia A. 

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

JOURNAL=Frontiers in Chemistry

VOLUME=9

YEAR=2021

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2021.643796

DOI=10.3389/fchem.2021.643796

ISSN=2296-2646

ABSTRACT=<p>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 <inline-formula id="inf1"><mml:math id="m1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>b</mml:mi><mml:msub><mml:mi>c</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:mrow></mml:math></inline-formula> 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<sub><italic>o</italic></sub>-site exclusively leaves the <inline-formula id="inf2"><mml:math id="m2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>b</mml:mi><mml:msub><mml:mi>c</mml:mi><mml:mn>1</mml:mn></mml:msub></mml:mrow></mml:math></inline-formula> 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.</p>