Effects of protein folding on metalloprotein redox-active sites: electron-transfer properties of blue and purple copper proteins

Abstract The tuning of the electron-transfer properties of the metal sites in blue and purple copper proteins by the protein fold is reviewed, with azurin and the Thermus Cu A domain as examples. These proteins have unique electronic and EPR spectra, which are ascribed to highly electron delocalized metal sites. The folding free energies of these proteins are higher in the oxidized compared to the reduced states, and as a consequence the reduction potentials of the unfolded proteins are higher than those of the native forms. The high potentials of the unfolded proteins are ascribed to maintenance of the core ligand structure of the metal site. In proteins with the folded forms having a higher potential than the unfolded forms, the potential is increased by hydrophobic encapsulation. In proteins with a lower potential of the folded forms, the high potential is down-tuned by different strengths of axial ligation, controlled by the protein fold.