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Titration Behavior of Residues at the Entrance of the D-Pathway of Cytochrome c Oxidase from Paracoccus denitrificans Investigated by Continuum Electrostatic Calculations

Elena Olkhova ^*, Volkhard Helms  and Hartmut Michel ^*

^* Max Planck Institute of Biophysics, Department of Molecular Membrane Biology, D-60438 Frankfurt, Germany; and Saarland University, Center for Bioinformatics, 66041, Saarbrücken, Germany

Correspondence: Address reprint requests to Volkhard Helms, University of Saarland, Center of Bioinformatics, Postfach 15 11 50, 66041, Saarbrücken, Germany. Tel.: 49-681-302-64165; Fax: 49-681-302-64180; E-mail: volkhard.helms{at}bioinformatik.uni-saarland.de.

Continuum electrostatic calculations were employed to investigate the titration curves of the fully oxidized state of wild type and several variants of cytochrome c oxidase from Paracoccus denitrificans (N131D, N131C, N131V, and D124N) for different values of the dielectric constant of the protein. The effects of the mutations at the entrance of the D-proton transfer pathway were found to be quite localized to their immediate surroundings. The results can be well interpreted in the light of the available biochemical and structural data and help understanding the effects of mutations on proton conductivity. The mutations of aspartic acid Asp-I-124 to a neutral residue resulted in a decreased pK_a value of His-I-28 suggesting that the mutation of His-I-28 may have a significant influence on the coupling of electron and proton transfer in cytochrome c oxidase. We also investigated the effect of the mutations N131D, N131C, and N131V on the residue Glu-I-278 in terms of its pK_a value and electrostatic interaction energies.

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