How Cytochromes with Different Folds Control Heme Redox Potentials

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Abstract
The electrochemical midpoint potentials (Em's) of 13 cytochromes, in globin (c, c2, c551, c553), four-helix bundle (c‘, b562), αβ roll (b5), and β sandwich (f) motifs, with Em's spanning 450 mV were calculated with multiconformation continuum electrostatics (MCCE). MCCE calculates changes in oxidation free energy when a heme−axial ligand complex is moved from water into protein. Calculated and experimental Em's are in good agreement for cytochromes with His−Met and bis-His ligated hemes, where microperoxidases provide reference Em's. In all cytochromes, Em's are raised by 130−260 mV relative to solvated hemes by the loss of reaction field (solvation) energy. However, there is no correlation between Em and heme surface exposure. Backbone amide dipoles in loops or helix termini near the axial ligands raise Em's, but amides in helix bundles contribute little. Heme propionates lower Em's. If the propionic acids are partially protonated in the reduced cytochrome, protons are released on heme oxidation, contributing to the pH dependence of the Em. In all cytochromes studied except b5's and low potential globins, buried side chains raise Em's. MCCE samples ionizable group protonation states, heme redox states, and side chain rotamers simultaneously. Globins show the largest structural changes on heme oxidation and four-helix bundles the least. Given the calculated protein-induced Em shift and measured cytochrome Em the five-coordinate, His heme in c‘ is predicted to have a solution Em between that of isolated bis-His and His−Met hemes, while the reference Em for His−Ntr ligands in cytochrome f should be near that of His−Met hemes.

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