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How oxygen gets there

Cytochrome c oxidase has alternative paths for oxygen diffusion to the active center

Oeiras, 9.12.2014

Given the importance of oxygen for life on this planet you would expect everything was known about how living organisms make use of it. But no one knows for instance how oxygen reaches the active center of cytochrome c oxidase, the enzyme actually using oxygen in aerobic respiration. Computational Biologists at ITQB (Protein Modelling and Molecular Simulation Labs) looked into how oxygen diffuses inside this enzyme, just to uncover two new paths that oxygen could take to reach the active center. The results challenge previous conclusions from the available structural data and are now published in PLoS Computational Biology.

Researchers gain insight into the mechanism of enzymes by looking at their tridimensional structure. The structure can be determined experimentally by NMR or X-ray diffraction but not all details are accessible to these techniques. This is where simulation methods step in. Starting from the structural data, researchers simulate diffusion mechanisms on the computer, both to complement the available information and to generate new hypothesis for experimentalists to test. This is what ITQB researchers did for cytochrome c oxidase, the terminal enzyme of the respiratory chain in bacteria and mitochondria. Cytochrome c oxidase catalyses the reduction of molecular oxygen to water, while generating a proton gradient necessary for storing energy in the form of ATP (the purpose of aerobic respiration in the first place). But for the reaction to occur, oxygen needs to access the enzyme active site, so the question is: how does it get there?

In a computational effort equivalent to 10.6 years of a single CPU, researchers tested the likelihood of oxygen to occupy every single space within the enzyme by calculating the energy associated with each position. The aim of all these calculations is to find adjoining low-energy (high probability) spaces, which could form a channel from the outside of the enzyme to its active center. Using this method, researchers noticed that the single channel predicted by the structural data had a high energy barrier close to the active center, making it an unlikely path. However, they could also identify two alternative and energetically favorable channels for oxygen to diffuse to the active center.

Data from the molecular simulations suggest that these new oxygen paths inside cytochrome c oxidase are not visible in the tridimensional structure because they are transient channels; the channels form as oxygen travels inside the enzyme, making its way through the flexible aminoacid residues as it moves inwards. By tinkering with specific aminoacid residues in cytochrome c oxidase, experimentalists should be able to test if oxygen uses these, for now hypothetical, channels and which one(s) it prefers.

Original Article

PLoS Computational Biology (2014) 10 (12): e1004010

Exploring O2 Diffusion in A-Type Cytochrome c Oxidases: Molecular Dynamics Simulations Uncover Two Alternative Channels towards the Binuclear Site

A. Sofia F. Oliveira, João M. Damas, António M. Baptista, Cláudio M. Soares

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