Influence of the dynamic interplay between protein and solvent on the redox properties of blue copper proteins

We used direct electrochemistry and MD simulations to investigate the redox reactivity of native azurin and four chimeric cupredoxins, in which the ligand-containing loop of azurin has been replaced either with that of other members of the blue copper family or with synthetic sequences featuring only Ala residues. It turns out that the dynamic interplay between protein and solvent is the key factor determining the redox properties of these hallmark ET systems. In particular, the dynamics of the small, metal-binding loop region controls the outer-sphere reorganization energy. The molecular determinants to the reduction potential were also investigated. Moreover, the dynamics between the protein scaffold and the surrounding solvent proved to be crucial in determining the pKa of the protonation of the C-terminal copper binding His in the reduced proteins.